Imidazo[4,5-C]pyridine and pyrrolo[2,3-C]pyridine derivatives as SSAO inhibitors

ABSTRACT

The compounds of formula (I) are inhibitors of semicarbazide-sensitive amine oxidase (SSAO) activity useful in the treatment of inflammation, an inflammatory disease, an immune or an autoimmune disorder, or inhibition of tumor growth.

This application is a national stage application under 35 U.S.C. §371 ofInternational Patent Application No. PCT/GB 2014/050765 filed Mar. 13,2014 and published as International Publication WO2014/140592, whichclaims priority to Great Britain Patent Application No. 1304526.5 filedMar. 13, 2013.

FIELD OF THE INVENTION

The present invention relates to compounds which are inhibitors of SSAOactivity. The invention also relates to pharmaceutical compositionscomprising these compounds and to the use of these compounds in thetreatment or prevention of medical conditions wherein inhibition of SSAOactivity is beneficial, such as inflammatory diseases, immune disordersand the inhibition of tumour growth.

BACKGROUND ART

Semicarbazide-sensitive amine oxidase (SSAO) activity is an enzymeactivity expressed by Vascular Adhesion Protein-1 (VAP-1) or AmineOxidase, Copper Containing 3 (AOC3), belongs to the copper-containingamine oxidase family of enzymes (EC.1.4.3.6). Therefore inhibitors ofthe SSAO enzyme may also modulate the biological functions of the VAP-1protein. Members of this enzyme family are sensitive to inhibition bysemicarbazide and utilize cupric ion and protein-derived topa quinone(TPQ) cofactor in the oxidative deamination of primary amines toaldehydes, hydrogen peroxide, and ammonia according to the followingreaction:R—CH₂—NH₂+O₂→R—CHO+H₂O₂+NH₃

Known substrates for human SSAO include endogenous methylamine andaminoacetone as well as some xenobiotic amines such as benzylamine[Lyles, Int. J. Biochem. Cell Biol. 1996, 28, 259-274; Klinman, Biochim.Biophys. Acta 2003, 1647(1-2), 131-137; Mátyus et al., Curr. Med. Chem.2004, 11(10), 1285-1298; O'Sullivan et al., Neurotoxicology 2004,25(1-2), 303-315]. In analogy with other copper-containing amineoxidases, DNA-sequence analysis and structure determination suggest thatthe tissue-bound human SSAO is a homodimeric glycoprotein consisting oftwo 90-100 kDa subunits anchored to the plasma membrane by a singleN-terminal membrane spanning domain [Morris et al., J. Biol. Chem. 1997,272, 9388-9392; Smith et al., J. Exp. Med. 1998, 188, 17-27; Airenne etal., Protein Science 2005, 14, 1964-1974; Jakobsson et al., ActaCrystallogr. D Biol. Crystallogr. 2005, 61(Pt 11), 1550-1562].

SSAO activity has been found in a variety of tissues including vascularand non-vascular smooth muscle tissue, endothelium, and adipose tissue[Lewinsohn, Braz. J. Med. Biol. Res. 1984, 17, 223-256; Nakos & Gossrau,Folia Histochem. Cytobiol. 1994, 32, 3-10; Yu et al., Biochem.Pharmacol. 1994, 47, 1055-1059; Castillo et al., Neurochem. Int. 1998,33, 415-423; Lyles & Pino, J. Neural. Transm. Suppl. 1998, 52, 239-250;Jaakkola et al., Am. J. Pathol. 1999, 155, 1953-1965; Morin et al., J.Pharmacol. Exp. Ther. 2001, 297, 563-572; Salmi & Jalkanen, TrendsImmunol. 2001, 22, 211-216]. In addition, SSAO protein is found in bloodplasma and this soluble form appears to have similar properties as thetissue-bound form [Yu et al., Biochem. Pharmacol. 1994, 47, 1055-1059;Kurkijärvi et al., J. Immunol. 1998, 161, 1549-1557]. It has recentlybeen shown that circulating human and rodent SSAO originates from thetissue-bound form [Göktürk et al., Am. J. Pathol. 2003, 163(5),1921-1928; Abella et al., Diabetologia 2004, 47(3), 429-438; Stolen etal., Circ. Res. 2004, 95(1), 50-57], whereas in other mammals theplasma/serum SSAO is also encoded by a separate gene called AOC4[Schwelberger, J. Neural. Transm. 2007, 114(6), 757-762].

The precise physiological role of this abundant enzyme has yet to befully determined, but it appears that SSAO and its reaction products mayhave several functions in cell signalling and regulation. For example,recent findings suggest that SSAO plays a role in both GLUT4-mediatedglucose uptake [Enrique-Tarancon et al., J. Biol. Chem. 1998, 273,8025-8032; Morin et al., J. Pharmacol. Exp. Ther. 2001, 297, 563-572]and adipocyte differentiation [Fontana et al., Biochem. J. 2001, 356,769-777; Mercier et al., Biochem. J. 2001, 358, 335-342]. In addition,SSAO has been shown to be involved in inflammatory processes where itacts as an adhesion protein for leukocytes [Salmi & Jalkanen, TrendsImmunol. 2001, 22, 211-216; Salmi & Jalkanen, in “Adhesion Molecules:Functions and Inhibition” K. Ley (Ed.), 2007, pp. 237-251], and mightalso play a role in connective tissue matrix development and maintenance[Langford et al., Cardiovasc. Toxicol. 2002, 2(2), 141-150; Göktürk etal., Am. J. Pathol. 2003, 163(5), 1921-1928]. Moreover, a link betweenSSAO and angiogenesis has recently been discovered [Noda et al., FASEBJ. 2008, 22(8), 2928-2935], and based on this link it is expected thatinhibitors of SSAO have an anti-angiogenic effect.

Several studies in humans have demonstrated that SSAO activity in bloodplasma is elevated in conditions such as congestive heart failure,diabetes mellitus, Alzheimer's disease, and inflammation [Lewinsohn,Braz. J. Med. Biol. Res. 1984, 17, 223-256; Boomsma et al., Cardiovasc.Res. 1997, 33, 387-391; Ekblom, Pharmacol. Res. 1998, 37, 87-92;Kurkijärvi et al., J. Immunol. 1998, 161, 1549-1557; Boomsma et al.,Diabetologia 1999, 42, 233-237; Meszaros et al., Eur. J. Drug Metab.Pharmacokinet. 1999, 24, 299-302; Yu et al., Biochim. Biophys. Acta2003, 1647(1-2), 193-199; Mátyus et al., Curr. Med. Chem. 2004, 11(10),1285-1298; O'Sullivan et al., Neurotoxicology 2004, 25(1-2), 303-315;del Mar Hernandez et al., Neurosci. Lett. 2005, 384(1-2), 183-187]. Themechanisms underlying these alterations of enzyme activity are notclear. It has been suggested that reactive aldehydes and hydrogenperoxide produced by endogenous amine oxidases contribute to theprogression of cardiovascular diseases, diabetic complications andAlzheimer's disease [Callingham et al., Prog. Brain Res. 1995, 106,305-321; Ekblom, Pharmacol. Res. 1998, 37, 87-92; Yu et al., Biochim.Biophys. Acta 2003, 1647(1-2), 193-199; Jiang et al., Neuropathol ApplNeurobiol. 2008, 34(2), 194-204]. Furthermore, the enzymatic activity ofSSAO is involved in the leukocyte extravasation process at sites ofinflammation where SSAO has been shown to be strongly expressed on thevascular endothelium [Salmi et al., Immunity 2001, 14(3), 265-276; Salmi& Jalkanen, in “Adhesion Molecules: Functions and Inhibition” K. Ley(Ed.), 2007, pp. 237-251]. Accordingly, inhibition of SSAO has beensuggested to have a therapeutic value in the prevention of diabeticcomplications and in inflammatory diseases [Ekblom, Pharmacol. Res.1998, 37, 87-92; Salmi et al., Immunity 2001, 14(3), 265-276; Salter-Cidet al., J. Pharmacol. Exp. Ther. 2005, 315(2), 553-562].

WO2007146188 teaches that blocking SSAO activity inhibits leucocyterecruitment, reduces the inflammatory response, and is expected to bebeneficial in prevention and treatment of seizures, for example, inepilepsy.

O'Rourke et al (J Neural Transm. 2007; 114(6):845-9) examined thepotential of SSAO inhibitors in neurological diseases, having previouslydemonstrated the efficacy of SSAO inhibition in a rat model of stroke.An SSAO inhibitor is tested on relapsing-remitting experimentalautoimmune encephalomyelitis (EAE), a mouse model that shares manycharacteristics with human multiple sclerosis. The data demonstrates thepotential clinical benefit of small molecule anti-SSAO therapy in thismodel and therefore in treatment of human multiple sclerosis.

SSAO knockout animals are phenotypically overtly normal but exhibit amarked decrease in the inflammatory responses evoked in response tovarious inflammatory stimuli [Stolen et al., Immunity 2005, 22(1),105-115]. In addition, antagonism of its function in wild type animalsin multiple animal models of human disease (e.g. carrageenan-induced pawinflammation, oxazolone-induced colitis, lipopolysaccharide-induced lunginflammation, collagen-induced arthritis, endotoxin-induced uveitis) bythe use of antibodies and/or small molecules has been shown to beprotective in decreasing the leukocyte infiltration, reducing theseverity of the disease phenotype and reducing levels of inflammatorycytokines and chemokines [Kirton et al., Eur. J. Immunol. 2005, 35(11),3119-3130; Salter-Cid et al., J. Pharmacol. Exp. Ther. 2005, 315(2),553-562; McDonald et al., Annual Reports in Medicinal Chemistry 2007,42, 229-243; Salmi & Jalkanen, in “Adhesion Molecules: Functions andInhibition” K. Ley (Ed.), 2007, pp. 237-251; Noda et al., FASEB J. 200822(4), 1094-1103; Noda et al., FASEB J. 2008, 22(8), 2928-2935]. Thisanti-inflammatory protection seems to be afforded across a wide range ofinflammatory models all with independent causative mechanisms, ratherthan being restricted to one particular disease or disease model. Thiswould suggest that SSAO may be a key nodal point for the regulation ofthe inflammatory response, and it is therefore likely that SSAOinhibitors will be effective anti-inflammatory drugs in a wide range ofhuman diseases. VAP-1 has also been implicated in the progression andmaintenance of fibrotic diseases including those of the liver and lung.Weston and Adams (J Neural Transm. 2011, 118(7), 1055-64) havesummarised the experimental data implicating VAP-1 in liver fibrosis,and Weston et al (EASL Poster 2010) reported that blockade of VAP-1accelerated the resolution of carbon tetrachloride induced fibrosis. Inaddition VAP-1 has been implicated in inflammation of the lung (e.g.Singh et al., 2003, Virchows Arch 442:491-495) suggesting that VAP-1blockers would reduce lung inflammation and thus be of benefit to thetreatment of cystic fibrosis by treating both the pro-fibrotic andpro-inflammatory aspects of the disease.

SSAO (VAP-1) is up regulated in gastric cancer and has been identifiedin the tumour vasculature of human melanoma, hepatoma and head and necktumours (Yoong K F, McNab G, Hubscher S G, Adams D H. (1998), J Immunol160, 3978-88; Irjala H, Salmi M, Alanen K, Gre'nman R, Jalkanen S(2001), Immunol. 166, 6937-6943; Forster-Horvath C, Dome B, Paku S, etal. (2004), Melanoma Res. 14, 135-40.). One report (Marttila-Ichihara F,Castermans K, Auvinen K, Oude Egbrink M G, Jalkanen S, Griffioen A W,Salmi M. (2010), J Immunol. 184, 3164-3173) has shown that mice bearingenzymically inactive VAP-1 grow melanomas more slowly, and have reducedtumour blood vessel number and diameter. The reduced growth of thesetumours was also reflected in the reduced (by 60-70%) infiltration ofmyeloid suppressor cells. Encouragingly VAP-1 deficiency had no effecton vessel or lymph formation in normal tissue.

Small molecules of different structural classes have previously beendisclosed as SSAO inhibitors, for example in WO 02/38153(tetrahydroimidazo[4,5-c]pyridine derivatives), in WO 03/006003(2-indanylhydrazine derivatives), in WO 2005/014530 (allylhydrazine andhydroxylamine (aminooxy) compounds) and in WO 2007/120528 (allylaminocompounds). Additional SSAO inhibitors are disclosed inPCT/EP2009/062011 and PCT/EP2009/062018. Additional SSAO inhibitors aredisclosed in PCT/GB2012/052265.

Patent application PCT/US2012/066153 (published as WO2013/078254)discloses compounds apparently useful as inhibitors of serine/threonineprotein kinases. The compounds are structurally related to the claimedcompounds, and have a bicyclic heteroaryl ring system substituted with aphenyl-cyclobutaneamine substituent.

The invention described here relates to a new class of SSAO inhibitorswith biological, pharmacological, and pharmacokinetic characteristicsthat make them suitable for use as prophylactic or therapeutic agents ina wide range of human inflammatory diseases and immune disorders. Thistherapeutic capacity is designed to block SSAO enzyme action, reducingthe levels of pro-inflammatory enzyme products (aldehydes, hydrogenperoxide and ammonia) whilst also decreasing the adhesive capacity ofimmune cells and correspondingly their activation and finalextra-vasation. Diseases where such an activity is expected to betherapeutically beneficial include all diseases where immune cells playa prominent role in the initiation, maintenance or resolution of thepathology, such as multiple sclerosis, arthritis and vasculitis.

DETAILED DESCRIPTION OF THE INVENTION

It has surprisingly been found that the compounds of formula (I) beloware inhibitors of SSAO. They are therefore useful for the treatment orprevention of diseases in which inhibition of SSAO activity isbeneficial, such as inflammation, inflammatory diseases, immune orautoimmune disorders, and inhibition of tumour growth.

According to a first aspect of the invention there is provided acompound of formula (I) or a pharmaceutically acceptable salt, orN-oxide thereof:

Wherein:

Y is selected from hydrogen, hydroxyl, —NH₂, —NH—C₁₋₄-alkyl,—NH-halo-C₁₋₄-alkyl, or —C₁₋₄-alkoxy;

Z is selected from hydrogen, halogen, hydroxyl, cyano, C₁₋₄-alkyl,halo-C₁₋₄-alkyl, C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy, —CONH₂, —SO₂NH₂, —NH₂,—NHC₁₋₄-alkyl, or —NHhalo-C₁₋₄-alkyl;

R¹ is a phenyl ring, or a 5 or 6-membered heteroaryl ring, either ringbeing optionally substituted with one or more substituents selected fromhalogen, cyano, C₁₋₄-alkyl, halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl, a 3-7membered cycloalkyl ring, —OR⁵, —NR^(4A)R^(4B), —NR⁶C(O)OR⁵, —NR⁶C(O)R⁵,—NR⁶C(O)NR^(4A)R^(4B), —C(O)NR^(4A)R^(4B), —C(O)R⁵, —C(O)OR⁵, and—NR⁶S(O)₂R⁵; wherein

R^(4A), R^(4B), R⁵ and R⁶ are each independently selected from hydrogen,C₁₋₄-alkyl or halo-C₁₋₄-alkyl, or

R^(4A) and R^(4B) together with the nitrogen to which they are attachedform a 3-7 membered cyclic amino group, optionally substituted by one ormore substituents selected from: halogen, hydroxyl, cyano, C₁₋₄-alkyl,halo-C₁₋₄-alkyl, C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy, —CONH₂, —SO₂NH₂, —NH₂,—NHC₁₋₄-alkyl, —NHhalo-C₁₋₄-alkyl;

X is selected from —N═ or —C(R²)═;

R² is selected from hydrogen, halogen, cyano, C₁₋₄-alkyl,halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl, —OR⁵, —NR^(4A)R^(4B), —NR⁶C(O)OR⁵,—NR⁶C(O)R⁵, —NR⁶C(O)NR^(4A)R^(4B), —C(O)NR^(4A)R^(4B), —C(O)R⁵,—C(O)OR⁵, —SO₂R⁵, —SO₂NR^(4A)R^(4B) and —NR⁶S(O)₂R⁵;

W is a phenyl ring or a 5 or 6-membered heteroaryl ring, either ringbeing optionally substituted with one or more substituents selected fromhalogen, cyano, oxo C₁₋₄-alkyl, halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl, —OR⁵,—NR^(7A)R^(7B), —NR⁶C(O)OR⁵, —NR⁶C(O)R⁵, —NR⁶C(O)NR^(7A)R^(7B),—C(O)NR^(7A)R^(7B), —C(O)R⁵, —C(O)OR⁵, —SO₂R⁵, —SO₂NR^(7A)R^(7B) and—NR⁶S(O)₂R⁵;

R^(7A) and R^(7B) are independently hydrogen, C₁₋₄-alkyl orhalo-C₁₋₄-alkyl.

V is selected from a bond, —O—, —N(R⁶)—, —(C═O)—, —CONR⁶—, —NR⁶C(O)—, or—C₁₋₄-alkylene-, wherein the C₁₋₄-alkylene group is optionallysubstituted by halogen, and wherein any one of the carbon atoms of theC₁₋₄-alkylene group may be replaced by —O— or —N(R⁶)—;

R³ is selected from hydrogen, —C₁₋₄-alkyl, —C₁₋₄-alkyl-C₁₋₄-alkoxy or a3-7 membered heterocyclic ring or 3-7 membered cycloalkyl ring, or a 5or 6-membered heteroaryl ring, any one of the rings being optionallysubstituted with one or more substituents selected from halogen, oxo,hydroxyl, cyano, C₁₋₄-alkyl, halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl, —OR⁵,—NR^(4A)R^(4B), —NR⁶C(O)OR⁵, —NR⁶C(O)R⁵, —NR⁶C(O)NR^(4A)R^(4B),—C(O)NR^(4A)R^(4B), —C(O)R⁵, —C(O)OR⁵, —SO₂R⁵, —SO₂NR^(4A)R^(4B) and—NR⁶S(O)₂R⁵;

with the proviso that groups —WVR³ and/or R¹ are not:

whereinn is 0, 1, or 2;R′ and R″ are independently selected from the group consisting of H,—C₁-C₆alkyl, —(C═O)—C₁-C₆ alkyl and —(C═O)OC(CH₃)₃; andR′″ is H, OH, or C₁-C₆ alkyl.And according to a second aspect of the invention there is provided acompound of formula (I) or a pharmaceutically acceptable salt, orN-oxide thereof

Wherein:

Y is selected from hydrogen, hydroxyl, —NH₂, —NH—C₁₋₄-alkyl,—NH-halo-C₁₋₄-alkyl, or —C₁₋₄-alkoxy;

Z is selected from hydrogen, halogen, hydroxyl, cyano, C₁₋₄-alkyl,halo-C₁₋₄-alkyl, C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy, —CONH₂, —SO₂NH₂, —NH₂,—NHC₁₋₄-alkyl, or —NHhalo-C₁₋₄-alkyl;

R¹ is a phenyl ring, or a 5 or 6-membered heteroaryl ring, either ringbeing optionally substituted with one or more substituents selected fromhalogen, cyano, C₁₋₄-alkyl, halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl, —OR⁵,—NR^(4A)R^(4B), —NR⁶C(O)OR⁵, —NR⁶C(O)R⁵, —NR⁶C(O)NR^(4A)R^(4B),—C(O)NR^(4A)R^(4B), —C(O)R⁵, —C(O)OR⁵, and —NR⁶S(O)₂R⁵; wherein

R^(4A), R^(4B), R⁵ and R⁶ are each independently selected from hydrogen,C₁₋₄-alkyl or halo-C₁₋₄-alkyl, or

R^(4A) and R^(4B) together with the nitrogen to which they are attachedform a 3-7 membered cyclic amino group, optionally substituted by one ormore substituents selected from: halogen, hydroxyl, cyano, C₁₋₄-alkyl,halo-C₁₋₄-alkyl, C₁₋₄-alkoxy, halo-C₁₋₄-alkoxy, —CONH₂, —SO₂NH₂, —NH₂,—NHC₁₋₄-alkyl, —NHhalo-C₁₋₄-alkyl;

X is selected from —N═ or —C(R²)═;

R² is selected from hydrogen, halogen, cyano, C₁₋₄-alkyl,halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl, —OR⁵, —NR^(4A)R^(4B), —NR⁶C(O)OR⁵,—NR⁶C(O)R⁵, —NR⁶C(O)NR^(4A)R^(4B), —C(O)NR^(4A)R^(4B), —C(O)R⁵,—C(O)OR⁵, —SO₂R⁵, —SO₂NR^(4A)R^(4B) and —NR⁶S(O)₂R⁵;

W is a phenyl ring or a 5 or 6-membered heteroaryl ring, either ringbeing optionally substituted with one or more substituents selected fromhalogen, cyano, C₁₋₄-alkyl, halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl, —OR⁵,—NR^(7A)R^(7B), —NR⁶C(O)OR⁵, —NR⁶C(O)R⁵, —NR⁶C(O)NR^(7A)R^(7B),—C(O)NR^(7A)R^(7B), —C(O)R⁵, —C(O)OR⁵, —SO₂R⁵, —SO₂NR^(7A)R^(7B) and—NR⁶S(O)₂R⁵;

R^(7A) and R^(7B) are independently hydrogen, C₁₋₄-alkyl orhalo-C₁₋₄-alkyl.

V is selected from a bond, —O—, —N(R⁶)—, —(C═O)—, —CONR⁶—, —NR⁶C(O)—, or—C₁₋₄-alkylene-, wherein the C₁₋₄-alkylene group is optionallysubstituted by halogen, and wherein any one of the carbon atoms of theC₁₋₄-alkylene group may be replaced by —O— or —N(R⁶)—;

R³ is hydrogen or a 3-7 membered heterocyclic ring or 3-7 memberedcycloalkyl ring selected from cyclopropyl, cyclopentyl or cyclohexyl, ora 5 or 6-membered heteroaryl ring, any one of the rings being optionallysubstituted with one or more substituents selected from halogen, oxo,hydroxyl, cyano, C₁₋₄-alkyl, halo-C₁₋₄-alkyl, cyano-C₁₋₄-alkyl, —OR⁵,—NR^(4A)R^(4B), —NR⁶C(O)OR⁵, —NR⁶C(O)R⁵, —NR⁶C(O)NR^(4A)R^(4B),—C(O)NR^(4A)R^(4B), —C(O)R⁵, —C(O)OR⁵, —SO₂R⁵, —SO₂NR^(4A)R^(4B) and—NR⁶S(O)₂R⁵.

In addition to the surprising activity of the compounds of formula (I)at the SSAO receptor, it has been surprisingly found that the claimedcompounds have surprisingly low activity at the hERG ion channel. Theperson skilled in the art, for example a medicinal chemist, understandsthat low hERG activity is an important property for a pharmaceuticaldrug compound. Without wishing to be bound by theory, it is believedthat the —WVR³ group as defined in claim 1 is especially advantageous inrelation to reduced hERG activity.

It is expected that compounds of the invention may be prepared in theform of hydrates, and solvates. Any reference herein, including theclaims herein, to “compounds with which the invention is concerned” or“compounds of the invention” or “the present compounds”, and the like,includes reference to salts, hydrates, and solvates of such compounds.The term ‘solvate’ is used herein to describe a molecular complexcomprising the compound of the invention and a stoichiometric amount ofone or more pharmaceutically acceptable solvent molecules, for example,ethanol. The term ‘hydrate’ is employed when said solvent is water.

Individual compounds of the invention may exist in an amorphous formand/or several polymorphic forms and may be obtained in differentcrystal habits. Any reference herein, including the claims herein, to“compounds with which the invention is concerned” or “compounds of theinvention” or “the present compounds”, and the like, includes referenceto the compounds irrespective of amorphous or polymorphic form.

Since compounds of the invention have a nitrogen atom in an aromaticring they may form N-oxides, and the invention includes compounds of theinvention in their N-oxide form.

DEFINITIONS

The following definitions shall apply throughout the specification andthe appended claims, unless otherwise stated or indicated.

The term “C₁₋₄-alkyl” denotes a straight or branched alkyl group havingfrom 1 to 4 carbon atoms. For parts of the range C₁₋₄-alkyl allsubgroups thereof are contemplated such as C₁₋₃-alkyl, C₁₋₂-alkyl,C₂₋₄-alkyl, C₂₋₃-alkyl and C₃₋₄-alkyl. Examples of said C₁₋₄-alkylinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyland tert-butyl.

Unless otherwise specified, the term “C₃₋₇-cycloalkyl” refers to amonocyclic saturated or partially unsaturated hydrocarbon ring systemhaving from 3 to 7 carbon atoms. Examples of said C₃₋₇-cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,cycloheptyl, and cycloheptenyl. For parts of the range “C₃₋₇-cycloalkyl”all subgroups thereof are contemplated such as C₃₋₇-cycloalkyl,C₃₋₆-cycloalkyl, C₃₋₅-cycloalkyl, C₃₋₄-cycloalkyl, C₄₋₇-cycloalkyl,C₄₋₆-cycloalkyl, C₄₋₅-cycloalkyl, C₅₋₇-cycloalkyl, C₅₋₆-cycloalkyl, andC₆₋₇-cycloalkyl.

The term “C₁₋₄-alkoxy” refers to a straight or branched C₁₋₄-alkyl groupwhich is attached to the remainder of the molecule through an oxygenatom. For parts of the range C₁₋₄-alkoxy, all subgroups thereof arecontemplated such as C₁₋₃-alkoxy, C₁₋₂-alkoxy, C₂₋₄-alkoxy, C₂₋₃-alkoxyand C₃₋₄-alkoxy. Examples of said C₁₋₄-alkoxy include methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

The term “haloC₁₋₄-alkoxy” refers to a straight or branched C₁₋₄-alkylgroup which is attached to the remainder of the molecule through anoxygen atom and has one or more hydrogen atoms thereof replaced withhalogen such as fluoro or chloro. For parts of the range C₁₋₄-alkoxy,all subgroups thereof are contemplated. Examples of said C₁₋₄-alkoxyinclude trifluoromethoxy.

The term “hydroxy-C₁₋₄-alkyl” denotes a straight or branched C₁₋₄-alkylgroup that has one or more hydrogen atoms thereof replaced with OH.Examples of said hydroxy-C₁₋₄-alkyl include hydroxymethyl,2-hydroxyethyl and 2,3-dihydroxypropyl.

The term “halo-C₁₋₄-alkyl” denotes a straight or branched C₁₋₄-alkylgroup that has one or more hydrogen atoms thereof replaced with halogen.Examples of said halo-C₁₋₄-alkyl include fluoromethyl, trifluoromethyl,trichloromethyl and 2-fluoroethyl.

The term “cyano-C₁₋₄-alkyl” denotes a straight or branched C₁₋₄-alkylgroup that has one or more hydrogen atoms thereof replaced with cyano.Examples of said cyano-C₁₋₄-alkyl include cyanomethyl, 2-cyanoethyl and3-cyanopropyl.

The term “amino-C₁₋₄-alkyl” denotes a straight or branched C₁₋₄-alkylgroup substituted with an amino group. Examples of said amino-C₁₋₄-alkylgroup include aminomethyl and 2-aminoethyl.

The term “C₁₋₄-alkylamino-C₁₋₄-alkyl” denotes an amino-C₁₋₄-alkyl groupas defined above, wherein the amino group is substituted with a straightor branched C₁₋₄-alkyl group. Examples of saidC₁₋₄-alkylamino-C₁₋₄-alkyl include methylaminoethyl andethylaminopropyl.

The term “di(C₁₋₄-alkyl)amino-C₁₋₄-alkyl” denotes an amino-C₁₋₄-alkylgroup as defined above, wherein the amino group is disubstituted withstraight or branched C₁₋₄-alkyl groups, which can be the same ordifferent. Examples of said di(C₁₋₄-alkyl)amino-C₁₋₄-alkyl includeN,N-dimethylaminomethyl, N-ethyl-N-methylaminoethyl andN,N-diethylaminomethyl.

The terms “heteroaryl” and “heteroaromatic ring” denote a monocyclicheteroaromatic ring comprising 5 to 6 ring atoms in which one or more ofthe ring atoms are other than carbon, such as nitrogen, sulphur oroxygen. Examples of heteroaryl groups include furyl, pyrrolyl, thienyl,oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridinyl,pyrimidinyl, tetrazolyl, pyrazolyl, pyridazinyl, pyrazinyl andthiadiazolyl.

The terms “heterocyclyl” and “heterocyclic ring” denote a non-aromatic,fully saturated or partially unsaturated, preferably fully saturated,monocyclic ring system having from 3 to 7 ring atoms, especially 5 or 6ring atoms, in which one or more of the ring atoms are other thancarbon, such as nitrogen, sulphur or oxygen. Examples of heterocyclicgroups include piperidinyl, morpholinyl, homomorpholinyl, azepanyl, piperazinyl, oxo-piperazinyl, diazepinyl, tertahydropyridinyl,tetrahydropyranyl, pyrrolidinyl, tertrahydrofuranyl, anddihydropyrrolyl, groups.

The term “heterocyclic-C₁₋₄-alkyl” refers to a heterocyclic ring that isdirectly linked to a straight or branched C₁₋₄-alkyl group via a carbonor nitrogen atom of said ring. Examples of said heterocyclic-C₁₋₄-alkylinclude piperidin-4-ylmethyl, piperidin-1-ylmethyl,morpholin-4-yl-methyl and piperazin-4-ylmethyl. The C₁₋₄-alkyl part,which includes methylene, ethylene, propylene or butylene, is optionallysubstituted by one or more substituents selected from halogen, amino,methoxy, or hydroxyl.

The term “C₁₋₄-alkylene” denotes a straight or branched divalentsaturated hydrocarbon chain having from 1 to 4 carbon atoms. TheC₁₋₄-alkylene chain may be attached to the rest of the molecule and tothe radical group through one carbon within the chain or through any twocarbons within the chain. Examples of C₁₋₄-alkylene radicals includemethylene [—CH₂—], 1,2-ethylene [—CH₂—CH₂—], 1,1-ethylene [—CH(CH₃)—],1,2-propylene [—CH₂—CH(CH₃)—] and 1,3-propylene [—CH₂—CH₂—CH₂—]. Whenreferring to a “C₁₋₄-alkylene” radical, all subgroups thereof arecontemplated, such as C₁₋₂-alkylene, C₂₋₃-alkylene, or C₃₋₄-alkylene.

“Halogen” refers to fluorine, chlorine, bromine or iodine, preferablyfluorine and chlorine, most preferably fluorine.

“Hydroxy” refers to the —OH radical.

“Cyano” refers to the —ON radical.

“Oxo” refers to the carbonyl group ═O.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not.

“Pharmaceutically acceptable” means being useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes being useful forveterinary use as well as human pharmaceutical use.

“Treatment” as used herein includes prophylaxis of the named disorder orcondition, or amelioration or elimination of the disorder once it hasbeen established.

“An effective amount” refers to an amount of a compound that confers atherapeutic effect on the treated subject. The therapeutic effect may beobjective (i.e., measurable by some test or marker) or subjective (i.e.,subject gives an indication of or feels an effect).

“Prodrugs” refers to compounds that may be converted under physiologicalconditions or by solvolysis to a biologically active compound of theinvention. A prodrug may be inactive when administered to a subject inneed thereof, but is converted in vivo to an active compound of theinvention. Prodrugs are typically rapidly transformed in vivo to yieldthe parent compound of the invention, e.g. by hydrolysis in the blood.The prodrug compound usually offers advantages of solubility, tissuecompatibility or delayed release in a mammalian organism (see Silverman,R. B., The Organic Chemistry of Drug Design and Drug Action, 2^(nd) Ed.,Elsevier Academic Press (2004), pp. 498-549). Prodrugs of a compound ofthe invention may be prepared by modifying functional groups, such as ahydroxy, amino or mercapto groups, present in a compound of theinvention in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent compound of theinvention. Examples of prodrugs include, but are not limited to,acetate, formate and succinate derivatives of hydroxy functional groupsor phenyl carbamate derivatives of amino functional groups.

Throughout the specification and the appended claims, a given chemicalformula or name shall also encompass all salts, hydrates, solvates,N-oxides and prodrug forms thereof. Further, a given chemical formula orname shall encompass all tautomeric and stereoisomeric forms thereof.Tautomers include enol and keto forms. Stereoisomers include enantiomersand diastereomers. Enantiomers can be present in their pure forms, or asracemic (equal) or unequal mixtures of two enantiomers. Diastereomerscan be present in their pure forms, or as mixtures of diastereomers.Diastereomers also include geometrical isomers, which can be present intheir pure cis or trans forms or as mixtures of those.

The compounds of formula (I) may be used as such or, where appropriate,as pharmacologically acceptable salts (acid or base addition salts)thereof. The pharmacologically acceptable addition salts mentioned beloware meant to comprise the therapeutically active non-toxic acid and baseaddition salt forms that the compounds are able to form. Compounds thathave basic properties can be converted to their pharmaceuticallyacceptable acid addition salts by treating the base form with anappropriate acid. Exemplary acids include inorganic acids, such ashydrogen chloride, hydrogen bromide, hydrogen iodide, sulphuric acid,phosphoric acid; and organic acids such as formic acid, acetic acid,propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolicacid, maleic acid, malonic acid, oxalic acid, benzenesulphonic acid,toluenesulphonic acid, methanesulphonic acid, trifluoroacetic acid,fumaric acid, succinic acid, malic acid, tartaric acid, citric acid,salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid,ascorbic acid and the like. Exemplary base addition salt forms are thesodium, potassium, calcium salts, and salts with pharmaceuticallyacceptable amines such as, for example, ammonia, alkylamines,benzathine, and amino acids, such as, e.g. arginine and lysine. The termaddition salt as used herein also comprises solvates which the compoundsand salts thereof are able to form, such as, for example, hydrates,alcoholates and the like.

The Group Y

In an embodiment Y is from hydrogen, hydroxyl, —NH₂, —NH—C₁₋₄-alkyl suchas —NH-Methyl, —NH-ethyl, or —NH-isopropyl, —NH-halo-C₁₋₄-alkyl such as—NHtrifluoromethyl, or —C₁₋₄-alkoxy such as methoxy. In an embodiment Yis hydrogen.

The Group Z

In an embodiment Z is hydrogen, halogen such as fluoro or chloro,hydroxyl, cyano, C₁₋₄-alkyl such as methyl or isopropyl, halo-C₁₋₄-alkylsuch as triflouromethyl, C₁₋₄-alkoxy such as methoxy, halo-C₁₋₄-alkoxysuch as trifluoromethoxy, —CONH₂, —SO₂NH₂, —NH₂, —NHC₁₋₄-alkyl such as—NH-Methyl, —NH-ethyl, or —NH-isopropyl, or —NHhalo-C₁₋₄-alkyl. In anembodiment Z is hydrogen.

The Group R¹

In an R¹ embodiment is a phenyl ring, or a 5 or 6-membered heteroarylring either ring being optionally substituted with one or moresubstituents selected from halogen such as fluoro or chloro, cyano,C₁₋₄-alkyl such as methyl or isopropyl, halo-C₁₋₄-alkyl such astrifluoromethyl, cyano-C₁₋₄-alkyl such as methylcyano, —OR⁵ such asmethoxy or trifluoromethoxy, —NR^(4A)R^(4B) such as —NH₂, —NHMethyl,—NHisopropyl, —NR⁶C(O)OR⁵, —NR⁶C(O)R⁵, —NR⁶C(O)NR^(4A)R^(4B),—C(O)NR^(4A)R^(4B), —C(O)R⁵ such as —COCH₃, —C(O)OR⁵, and —NR⁶S(O)₂R⁵.In an embodiment R¹ is optionally substituted phenyl, pyridyl, pyrrole,furan, imidazole, or thiophene.

In an embodiment R¹ is a phenyl ring, or a 5 or 6-membered heteroarylring substituted with a 3-7 membered cycloalkyl group such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; preferablycyclopropyl.

R^(4A), R^(4B), R⁵ and R⁶ are each independently selected from hydrogen,C₁₋₄-alkyl such as methyl, ethyl or isopropyl, or halo-C₁₋₄-alkyl suchas trifluoromethyl, or

R^(4A) and R^(4B) together with the nitrogen to which they are attachedform a 3-7 membered cyclic amino group such as aziridine, azetidine,oxetane, pyrrolidine, piperidine, piperazine, homopiperidine,homopiperazine, morpholine, or tetrahydrofuran, optionally substitutedby one or more substituents selected from: halogen such as fluoro orchloro, hydroxyl, cyano, C₁₋₄-alkyl such as methyl or isopropyl,halo-C₁₋₄-alkyl such as triflouromethyl, C₁₋₄-alkoxy such as methoxy,halo-C₁₋₄-alkoxy such as trifluoromethoxy, —CONH₂, —SO₂NH₂, —NH₂,—NHC₁₋₄-alkyl, —NHhalo-C₁₋₄-alkyl;

The Group X

In an embodiment X is selected from —N═ or —C(R²)═;

The Group R²

In an embodiment R² is hydrogen, halogen such as fluoro or chloro,cyano, C₁₋₄-alkyl such as methyl or ethyl or isopropyl, halo-C₁₋₄-alkylsuch as trifluoromethyl. In an embodiment R² is hydrogen.

The Group W

In an embodiment W is a phenyl ring. In an alternative embodiment W a6-membered heterocyclic ring selected from pyridine, pyridazine,pyrazine, or pyrimidine. In an alternative embodiment W is a 5-memberedring selected from oxazole, thiazole or imidazole. In an embodiment W isimidazolyl and the imidazolyl ring is connected to the pyrrolopyridinecore (i.e. the rest of the molecule) via an imidazolyl ring carbon atom.In an embodiment W is a pyrazole ring.

Any of the aforementioned rings are optionally substituted with one ormore substituents as defined in claim 1. In an embodiment W issubstituted with one or more groups selected from fluoro, chloro, cyano,methyl or trifluoromethyl.

In an embodiment W is a divalent group selected from any one of thefollowing rings, any of which rings is optionally substituted with oneor more substituents as defined in relation to formula (I).

wherein the bond marked ** is directly connected to the rest of themolecule and the atom marked * is directly connected to V.

The Group V

In an embodiment V is selected from a bond, —O—, —N(R⁶)— such as —NH— or—N(CH₃)—, —(C═O)—, —CONR⁶— such as —CONH— or —CON(CH₃)—, —NR⁶C(O)— suchas —NHC(O)— or —N(CH₃)C(O)—, or —C₁₋₄-alkylene-, wherein theC₁₋₄-alkylene group is optionally substituted by halogen such as fluoroor chloro, and wherein any one of the carbon atoms of the C₁₋₄-alkylenegroup may be replaced by —O— or —N(R⁶)— such as —CH₂O— in eitherdirection or —CH₂—NH—; —CH₂—N(CH₃)— in either direction.

The Group R³

In an embodiment R³ is hydrogen. In an alternative embodiment R³ anoptionally substituted 3-7 membered heterocyclic ring such as aziridine,azetidine, oxetane, pyrrolidine, piperidine, piperazine, homopiperidine,homopiperazine, morpholine, or tetrahydrofuran. In an embodiment R³ isan optionally substituted 3-7 membered cycloalkyl ring such ascyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In an alternativeembodiment R³ is an optionally substituted 5 or 6-membered heteroarylring such as imidazole, phenyl, pyridine, thiophene. The optionalsubstituents are defined in formula (I). In an embodiment any one of therings is optionally substituted with one or more substituents selectedfrom halogen such as fluoro or chloro, oxo, hydroxyl, cyano, C₁₋₄-alkylsuch as methyl, ethyl, propyl, t-butyl, or isopropyl, halo-C₁₋₄-alkylsuch as trifluoromethyl, cyano-C₁₋₄-alkyl, —OR⁵ such as methoxy ortrifluoromethoxy, —NR^(4A)R^(4B) such as —NH₂, NHmethyl, or morpholineor piperidine, —NR⁶C(O)OR⁵, —NR⁶C(O)R⁵, —NR⁶C(O)NR^(4A)R^(4B),—C(O)NR^(4A)R^(4B), —C(O)R⁵, —C(O)OR⁵, —SO₂R⁵, —SO₂NR^(4A)R^(4B) and—NR⁶S(O)₂R⁵.

In an embodiment R³ is selected from the following ring systems:

Wherein R⁸ is selected from hydrogen, CH₃, —CONH₂, —NHCONH₂, —S(O)₂CH₃,—COCH₃.

In an embodiment R³ is selected from the following ring systems:

In an embodiment R³ is selected from hydrogen, —C₁₋₄-alkyl such asmethyl, ethyl, propyl and isopropyl, and —C₁₋₄-alkyl-C₁₋₄-alkoxy such as—(CH₂)₂OCH₃.

In an embodiment the group —VR³ is selected from:

wherein R¹⁵ is hydrogen or methyl.In an embodiment, the invention includes a compound of formula (Xa)

wherein E is —C═ or —N═,R⁹ and R¹⁰ are each independently one or more substituents selected fromhydrogen, halogen, cyano, oxo, C₁₋₄-alkyl such as methyl, —OC₁₋₄-alkylsuch as OCH₃, and halo-C₁₋₄-alkyl; andR¹¹ is one or more substituents selected from hydrogen, halogen such asfluoro and/or chloro, cyano, cyclopropyl, C₁₋₄-alkyl such as methyl, andhalo-C₁₋₄-alkyl.

In one aspect, the invention relates to a compound of formula (I) foruse in therapy. The compounds as defined above are useful as inhibitorsof SSAO activity. As such, they are useful in the treatment orprevention of conditions and diseases in which inhibition of SSAOactivity is beneficial. More specifically, they are useful for thetreatment or prevention of inflammation, inflammatory diseases, immuneor autoimmune disorders, cystic fibrosis, or inhibition of tumourgrowth; and they are useful in the manufacture of a medicament fortreatment or prevention of inflammation, inflammatory diseases, immuneor autoimmune disorders, cystic fibrosis, or inhibition of tumour growth

In particular, it is believed that compounds of formula (I) are usefulfor the treatment or prevention of arthritis (such as rheumatoidarthritis, juvenile rheumatoid arthritis, osteoarthritis and psoriaticarthritis), synovitis, vasculitis, conditions associated withinflammation of the bowel (such as Crohn's disease, ulcerative colitis,inflammatory bowel disease and irritable bowel syndrome),atherosclerosis, multiple sclerosis, Alzheimer's disease, vasculardementia, pulmonary inflammatory diseases (such as asthma, chronicobstructive pulmonary disease and acute respiratory distress syndrome),fibrotic diseases (including idiopathic pulmonary fibrosis, cardiacfibrosis and systemic sclerosis (scleroderma)), inflammatory diseases ofthe skin (such as contact dermatitis, atopic dermatitis and psoriasis),systemic inflammatory response syndrome, sepsis, inflammatory and/orautoimmune conditions of the liver (such as autoimmune hepatitis,primary biliary cirrhosis, alcoholic liver disease, sclerosingcholangitis, and autoimmune cholangitis), diabetes (type I or II) and/orthe complications thereof, chronic heart failure, congestive heartfailure, ischemic diseases (such as stroke and ischemia-reperfusioninjury), and myocardial infarction and/or the complications thereof, orepilepsy.

It is believed that the compounds of the invention are especially usefulfor the treatment or prevention of vasculitis, including, but notlimited to, giant cell arteritis, Takayasu's arteritis, Polyarteritisnodosa, Kawasaki disease, Wegener's granulomatosis, Churg-Strausssyndrome, microscopic polyangiitis, Henoch-Schönlein purpura,cryoglobulinemia, cutaneous leukocytoclastic angiitis and primaryangiitis of the central nervous system.

It is also believed that the compounds of the invention are especiallyuseful for the treatment of rheumatoid arthritis, chronic obstructivepulmonary disease or atopic dermatitis.

In view of the evidence cited in the above introduction that VAP-1 is upregulated in several cancers, including gastric cancer, melanoma,hepatoma and head and neck tumours and that mice bearing enzymaticallyinactive VAP-1 grow melanomas more slowly, and in view of the linkbetween VAP-1 and angiogenesis, it is also expected that the compoundsof the invention are anti-angiogenic and therefore have utility in thetreatment of cancers by inhibition of tumour growth.

The invention thus includes the compounds of formula (I) above for usein the treatment or prevention of the above-mentioned conditions anddiseases. The invention also includes the use of said compounds in themanufacture of a medicament for the treatment or prevention of theabove-mentioned conditions and diseases. The invention furthermoreincludes methods for treatment or prevention of such conditions anddiseases, comprising administering to a mammal, including man, in needof such treatment an effective amount of a compound as defined above.

Methods delineated herein include those wherein the subject isidentified as in need of a particular stated treatment. Identifying asubject in need of such treatment can be in the judgment of a subject ora health care professional and can be subjective (e.g. opinion) orobjective (e.g. measurable by a test or diagnostic method).

In other aspects, the methods herein include those further comprisingmonitoring subject response to the treatment administrations. Suchmonitoring may include periodic sampling of subject tissue, fluids,specimens, cells, proteins, chemical markers, genetic materials, etc. asmarkers or indicators of the treatment regimen. In other methods, thesubject is prescreened or identified as in need of such treatment byassessment for a relevant marker or indicator of suitability for suchtreatment.

In one embodiment, the invention provides a method of monitoringtreatment progress. The method includes the step of determining a levelof diagnostic marker (Marker) (e.g., any target or cell type delineatedherein modulated by a compound herein) or diagnostic measurement (e.g.,screen, assay) in a subject suffering from or susceptible to a disorderor symptoms thereof delineated herein, in which the subject has beenadministered a therapeutic amount of a compound herein sufficient totreat the disease or symptoms thereof. The level of Marker determined inthe method can be compared to known levels of Marker in either healthynormal controls or in other afflicted patients to establish thesubject's disease status. In preferred embodiments, a second level ofMarker in the subject is determined at a time point later than thedetermination of the first level, and the two levels are compared tomonitor the course of disease or the efficacy of the therapy. In certainpreferred embodiments, a pre-treatment level of Marker in the subject isdetermined prior to beginning treatment according to this invention;this pre-treatment level of Marker can then be compared to the level ofMarker in the subject after the treatment commences, to determine theefficacy of the treatment.

In certain method embodiments, a level of Marker or Marker activity in asubject is determined at least once. Comparison of Marker levels, e.g.,to another measurement of Marker level obtained previously orsubsequently from the same patient, another patient, or a normalsubject, may be useful in determining whether therapy according to theinvention is having the desired effect, and thereby permittingadjustment of dosage levels as appropriate. Determination of Markerlevels may be performed using any suitable sampling/expression assaymethod known in the art or described herein. Preferably, a tissue orfluid sample is first removed from a subject. Examples of suitablesamples include blood, urine, tissue, mouth or cheek cells, and hairsamples containing roots. Other suitable samples would be known to theperson skilled in the art. Determination of protein levels and/or mRNAlevels (e.g., Marker levels) in the sample can be performed using anysuitable technique known in the art, including, but not limited to,enzyme immunoassay, ELISA, radiolabeling/assay techniques,blotting/chemiluminescence methods, real-time PCR, and the like.

Compositions

A currently preferred embodiment of the invention is a pharmaceuticalcomposition comprising a compound of formula (I), together with one ormore pharmaceutically acceptable carriers and/or excipients.

For clinical use, the compounds of the invention are formulated intopharmaceutical formulations for various modes of administration. It willbe appreciated that compounds of the invention may be administeredtogether with a physiologically acceptable carrier, excipient, ordiluent. The pharmaceutical compositions of the invention may beadministered by any suitable route, preferably by oral, rectal, nasal,topical (including buccal and sublingual), sublingual, transdermal,intrathecal, transmucosal or parenteral (including subcutaneous,intramuscular, intravenous and intradermal) administration.

Other formulations may conveniently be presented in unit dosage form,e.g., tablets and sustained release capsules, and in liposomes, and maybe prepared by any methods well known in the art of pharmacy.Pharmaceutical formulations are usually prepared by mixing the activesubstance, or a pharmaceutically acceptable salt thereof, withconventional pharmaceutically acceptable carriers, diluents orexcipients. Examples of excipients are water, gelatin, gum arabicum,lactose, microcrystalline cellulose, starch, sodium starch glycolate,calcium hydrogen phosphate, magnesium stearate, talcum, colloidalsilicon dioxide, and the like. Such formulations may also contain otherpharmacologically active agents, and conventional additives, such asstabilizers, wetting agents, emulsifiers, flavouring agents, buffers,and the like. Usually, the amount of active compounds is between 0.1-95%by weight of the preparation, preferably between 0.2-20% by weight inpreparations for parenteral use and more preferably between 1-50% byweight in preparations for oral administration.

The formulations can be further prepared by known methods such asgranulation, compression, microencapsulation, spray coating, etc. Theformulations may be prepared by conventional methods in the dosage formof tablets, capsules, granules, powders, syrups, suspensions,suppositories or injections. Liquid formulations may be prepared bydissolving or suspending the active substance in water or other suitablevehicles. Tablets and granules may be coated in a conventional manner.To maintain therapeutically effective plasma concentrations for extendedperiods of time, compounds of the invention may be incorporated intoslow release formulations.

The dose level and frequency of dosage of the specific compound willvary depending on a variety of factors including the potency of thespecific compound employed, the metabolic stability and length of actionof that compound, the patient's age, body weight, general health, sex,diet, mode and time of administration, rate of excretion, drugcombination, the severity of the condition to be treated, and thepatient undergoing therapy. The daily dosage may, for example, rangefrom about 0.001 mg to about 100 mg per kilo of body weight,administered singly or multiply in doses, e.g. from about 0.01 mg toabout 25 mg each. Normally, such a dosage is given orally but parenteraladministration may also be chosen.

Preparation of Compounds of the Invention

The compounds of formula (I) above may be prepared by, or in analogywith, conventional methods. The preparation of intermediates andcompounds according to the examples of the present invention may inparticular be illuminated by the following Schemes. Definitions ofvariables in the structures in schemes herein are commensurate withthose of corresponding positions in the formulas delineated herein.

wherein V, W, X, Y, Z, R¹, R² and R³ are as defined in formula (I);

Compounds of general formula (I) where X is N (designated compounds ofgeneral formula (Ia)), can easily be prepared by a number of alternativeroutes. For example, 3-bromo-4-nitropyridine N-oxides of general formula(IIa) can undergo SnAr displacement with R¹NH₂ amines to give compoundsof general formula (IIIa), which can in turn be reductively cyclised togive compounds of general formula (Ia). Alternatively,3-fluoro-4-nitropyridines of general formula (IVa) can undergo SnArdisplacement with R¹NH₂ amines to give compounds of general formula(Va), which can in turn be reductively cyclised to give compounds ofgeneral formula (Ia). Alternatively, compounds of general formula (IIIa)can be reduced to pyridine-3,4-diamines of general formula (VIa).Compounds of general formula (VIa) can then undergo amide formation withcarboxylic acids of general formula (VIIa) to give amides of generalformula (VIIIa) which can be cyclised to give compounds of generalformula (Ia).

Optionally, the group W—V—R³ can be built up sequentially using standardchemistry methodologies including amide, urea and sulphonamideformation. If required, standard protecting group strategies can beemployed to facilitate the synthesis.

Optionally, a compound of formula (Ia) can also be transformed intoanother compound of formula (Ia) in one or more synthetic steps.

wherein V, W, X, Y, Z, R¹, R² and R³ are as defined in formula (I);

Compounds of general formula (I) where X is CR² (designated compounds ofgeneral formula (Ib)), can easily be prepared standard means. Forexample, 6-azaindoles of general formula (IIb) can be N-arylated withR¹—I iodides to give compounds of general formula (IIIb) which can inturn be converted to compounds of general formula (Ib) by boronateformation and subsequent Suzuki coupling.

Optionally, the group W—V—R³ can be built up sequentially using standardchemistry methodologies including amide, urea and sulphonamideformation. If required, standard protecting group strategies can beemployed to facilitate the synthesis.

Optionally, a compound of formula (Ib) can also be transformed intoanother compound of formula (Ib) in one or more synthetic steps.

The following abbreviations have been used:

-   -   Ac acetyl    -   aq aqueous    -   Boc tertiary-butyloxycarbonyl    -   calcd calculated    -   d day(s)    -   DCM dichloromethane    -   DIPEA diisopropylethylamine    -   DMA dimethylacetamide    -   DMF dimethylformamide    -   DMSO Dimethyl sulfoxide    -   EDC N-(3-dimethylaminopropyl)-N-ethylcarbodiimide    -   ES⁺ electrospray ionization    -   Et₃N triethylamine    -   EtOAc ethyl acetate    -   EtOH ethanol    -   Ex Example    -   h hour(s)    -   HATU O-(7-azabenzotriazol-1-yl)-N,N,N.,N.-tetramethyluronium        hexafluorophosphate    -   HBTU O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro        phosphate    -   HPLC High Performance Liquid Chromatography    -   Int Intermediate    -   LCMS Liquid Chromatography Mass Spectrometry    -   LDA Lithium diisopropylamide    -   M molar    -   MeCN acetonitrile    -   MeOH methanol    -   [MH]⁺ protonated molecular ion    -   Min minute(s)    -   NMP 1-methyl-2-pyrrolidinone    -   QTOF Quadrupole time-of-flight mass spectrometer    -   RP reverse phase    -   RT room temperature    -   Rt retention time    -   sat saturated    -   TFA trifluoroacetic acid    -   THF Tetrahydrofuran    -   UV Ultra violet    -   XPhos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

EXAMPLES AND INTERMEDIATE COMPOUNDS Experimental Methods

Reactions were conducted at room temperature unless otherwise specified.Microwave reactions were performed with a Biotage microwave reactorusing process vials fitted with aluminium caps and septa. Preparativechromatography was performed using a Flash Master Personal systemequipped with Isolute Flash II silica columns or using a CombiFlashCompanion system equipped with GraceResolv silica column. Reverse PhaseHPLC was performed on a Gilson system with a UV detector equipped withPhenomenex Synergi Hydro RP 150×10 mm, or YMC ODS-A 100/150×20 mmcolumns. The purest fractions were collected, concentrated and driedunder vacuum. Compounds were typically dried in a vacuum oven at 40° C.prior to purity analysis. Compound analysis was performed by HPLC/LCMSusing an Agilent 1100 HPLC system/Waters ZQ mass spectrometer connectedto an Agilent 1100 HPLC system with a Phenomenex Synergi, RP-Hydrocolumn (150×4.6 mm, 4 um, 1.5 mL per min, 30° C., gradient 5-100% MeCN(⁺0.085% TFA) in water (⁺0.1% TFA) over 7 min, 200-300 nm). Accuratemasses were measured using a Waters QTOF electrospray ion source andcorrected using Leucine Enkephalin lockmass. Spectra were acquired inpositive and negative electrospray mode. The acquired mass range was m/z100-1000. Test compounds were dissolved in DMSO to give a 10 mM stocksolution. Typically 5 mL of the DMSO stock were diluted with 495 mL ofacetonitrile and then further diluted with acetonitrile and water (1:1)to give a final concentration of 0.2 mM. The mass values reportedcorrespond either to the parent molecule with a hydrogen added [MH] orwith a hydrogen subtracted [M-H]. The compounds prepared were namedusing IUPAC nomenclature.

Intermediate 1 3-[(4-Chlorophenyl)amino]-4-nitropyridin-1-ium-1-olate

3-Bromo-4-nitropyridine N-oxide (1.00 g, 4.57 mmol) and 4-chloroaniline(1.75 g, 13.7 mmol) were dissolved in EtOH and heated at 60° C. for 18h. The reaction mixture was cooled to 0° C. and the precipitate wascollected by filtration and washed with cold EtOH to give the titlecompound as an orange solid (317 mg, 26.1%). LCMS (ES⁺): 266.1 [MH]⁺.HPLC: Rt 5.44 min, 99.5% purity.

Intermediates 2-3

Intermediates 2-3 were prepared similarly to Intermediate 1, by couplingof 3-bromo-4-nitropyridine N-oxide with the appropriate aniline; seeTable 1 below.

TABLE 1 SnAr formation of anilines

Form, Yield, LCMS, Int Structure Name HPLC 2

3-[(4-Fluorophenyl) amino]- 4-nitropyridin- 1-ium-1-olate Orange solidYield 2.66 g, 46.7% LCMS (ES⁺): 250.1 [MH]⁺ HPLC: Rt 5.00 min, 97.3%purity 3

3-[(4-Fluoro-4- methylphenyl) amino]-4- nitropyridin- 1-ium-1-olateOrange solid Yield 200 mg, 5.55% LCMS (ES⁺): 264.0 [MH]⁺ HPLC: Rt 5.52min, 93.2% purity

Intermediate 43-[(4-Fluoro-2-methylphenyl)amino]-4-nitropyridin-1-ium-1-olate

3-Fluoro-4-nitropyridine N-oxide (1.00 g, 6.33 mmol) and4-fluoro-2-methylaniline (2.42 mL, 25.3 mmol) were dissolved in EtOH (12mL) and heated at 90° C. for 16 h. The reaction mixture was cooled toRT, the precipitate was collected by filtration and washed with coldEtOH (10 mL) to give the title compound (1.60 g, 96.2%) as a yellowsolid. LCMS (ES⁺): 264.1 [MH]⁺. HPLC: Rt 5.56 min, 95.9% purity.

Intermediates 5-12

Intermediates 5-12 were prepared similarly to Intermediate 4, bycoupling of 3-fluoro-4-nitropyridine N-oxide with the appropriateaniline; see Table 2 below.

TABLE 2 SnAr formation of anilines

Form, Yield, LCMS, Int Structure Name HPLC 5

3-[(2-Chloro-4- fluorophenyl)amino]-4- nitropyridin-1-ium-1-olate Yellowsolid Yield 1.93 g, 53.9% LCMS (ES⁺): 284.2 [MH]⁺ HPLC: Rt 5.67 min,96.0% purity 6

3-[(4-Methylphenyl)amino]- 4-nitropyridin-1-ium-1-olate Orange solidYield 1.12 g, 96.2% LCMS (ES⁺): 246.1 [MH]⁺ HPLC: Rt 5.65 min, 99.3%purity 7

3-[(6-Methylpyridin-3- yl)amino]-4-nitropyridin-1- ium-1-olate Orangesolid Yield 1.04 g, 89.0% LCMS (ES⁺): 247.0 [MH]⁺ HPLC: Rt 2.86 min,64.5% purity 8

3-[(4-Bromophenyl)amino]- 4-nitropyridin-1-ium-1-olate Orange solidYield 1.55 g, crude LCMS (ES⁺): 309.9 [MH]⁺ HPLC: Rt 5.66 min, 95.8%purity 9

3-[(2-Fluorophenyl)amino]- 4-nitropyridin-1-ium-1-olate Orange solidYield 1.08 g, 91.3% LCMS (ES⁺): 250.0 [MH]⁺ HPLC: Rt 5.14 min, 100%purity 10

3-[(4- Hydroxyphenyl)amino]-4- nitropyridin-1-ium-1-olate Dark orangesolid Yield 1.40 g, crude LCMS (ES⁺): 248.0 [MH]⁺ HPLC: Rt 4.25 min,96.8% purity 11

4-Nitro-3-{[4- (trifluoromethyl)phenyl] amino}pyridin-1-ium-1-olateOrange solid Yield 1.38 g, 97.3% LCMS (ES⁺): 300.0 [MH]⁺ HPLC: Rt 5.84min, 93.8% purity 12

3-[(2,4- Difluorophenyl)amino]-4- nitropyridin-1-ium-1-olate Yellowsolid Yield 2.16 g, 63.9% LCMS (ES⁺): 268.0 [MH]⁺ HPLC: Rt 5.14 min,99.3% purity

Intermediate 13 N-(4-Chloro-3-fluorophenyl)-4-nitropyridin-3-amine

NaH (422 mg, 60% dispersion in mineral oil, 10.6 mmol) was suspended inTHF (20 mL) and 4-chloro-3-fluoroaniline (1.54 g, 10.6 mmol) and3-fluoro-4-nitropyridine (500 mg, 3.52 mmol) were added. The reactionmixture was stirred for 18 h, quenched with sat. aq. NH₄Cl (2 mL), andconcentrated in vacuo. The residue was partitioned between water (50 mL)and DCM (50 mL) and the organic fraction was dried (MgSO₄) andconcentrated in vacuo. The residue was purified by column chromatographyto give the title compound (207 mg, 22.0%) as an orange solid. LCMS(ES⁺): 268.0 [MH]⁺.

Intermediates 14-18

Intermediates 14-18 were prepared similarly to Intermediate 13, bycoupling of 3-fluoro-4-nitropyridine with the appropriate aniline; seeTable 3 below.

TABLE 3 SnAr formation of anilines

Form, Yield, LCMS, Int Structure Name HPLC 14

N-(5- Chloropyridin- 2-yl)-4- nitropyridin- 3-amine Orange gum Yield 221mg, 25.1% LCMS (ES⁺): 251.1 [MH]⁺ HPLC: Rt 5.99 min, 93.6% purity 15

5-Fluoro-N- (4-nitropyridin- 3-yl)pyridin- 2-amine Orange solid Yield441 mg, 53.5% LCMS (ES⁺): 235.0 [MH]⁺ HPLC: Rt 5.40 min, 95.2% purity 16

N-(4-Chloro-2- fluorophenyl)-4- nitropyridin- 3-amine Orange solid Yield1.26 g, 66.9% LCMS (ES⁺): 268.1 [MH]⁺ 17

N-(2,4- Difluorophenyl)-4- nitropyridin- 3-amine Orange solid Yield 752mg, 42.5% LCMS (ES⁺): 252.0 [MH]⁺ HPLC: Rt 5.91 min, 77.8% purity 18

5-Methyl-N- (4-nitropyridin- 3-yl)pyridin- 2-amine Dark red solid Yield611 mg, 37.7% LCMS (ES⁺): 231.1 [MH]⁺ HPLC: Rt 4.61 min, 97.5% purity

Intermediate 19 3-N-(4-Chlorophenyl)pyridine-3,4-diamine

Intermediate 1 (317 mg, 1.19 mmol) was dissolved in AcOH (10 mL) andiron powder (333 mg, 5.97 mmol) was added. The reaction mixture washeated at reflux for 1 h, diluted with water (50 mL), basified withNa₂CO₃ and extracted into DCM (3×50 mL). The combined organic fractionswere dried (MgSO₄) and concentrated in vacuo to give the title compoundas a red gum (254 mg, 96.9%). LCMS (ES⁺): 220.2 [MH]⁺. HPLC: Rt 4.31min, 99.5% purity.

Intermediate 20 3-N-(4-Fluorophenyl)pyridine-3,4-diamine

Intermediate 20 was prepared similarly to Intermediate 19, usingIntermediate 2 instead of Intermediate 1, to give the title compound(6.33 g, 91.3%) as a brown solid. LCMS (ES⁺): 204.1 [MH]⁺.

Intermediate 21 3-N-(4-Methylphenyl)pyridine-3,4-diamine

Intermediate 6 (6.00 g, 24.5 mmol) and ammonium formate (12.3 g, 196mmol) were suspended in EtOH (200 mL), Raney Nickel (50% slurry inwater; 11.0 mL) was added and the reaction mixture was heated at 85° C.for 2 h, filtered through Celite and concentrated in vacuo. The residuewas partitioned between water (150 mL) and DCM/MeOH (150 mL/20 mL) andthe aqueous fraction was extracted with DCM (100 mL). The combinedorganic fractions were dried (MgSO₄) and concentrated in vacuo to givethe title compound (3.20 g, 65.6%) as a blue solid. LCMS (ES⁺): 200.1[MH]⁺.

Intermediate 22 3-N-(4-Chloro-2-fluorophenyl)pyridine-3,4-diamine

Intermediate 22 was prepared similarly to Intermediate 21, usingIntermediate 16 instead of Intermediate 6, to give the title compound(509 mg, 31.7%) as an orange solid. LCMS (ES⁺): 238.1 [MH]⁺.

Intermediate 23 3-N-(6-Methylpyridin-3-yl)pyridine-3,4-diamine

Intermediate 7 (1.40 g, 5.69 mmol) and hydrazine monohydrate (1.11 mL,22.8 mmol) were suspended in THF (20 mL) and EtOH (20 mL), Raney nickel(˜50% slurry in water; 2 mL) was added slowly at 0° C. and the reactionmixture was warmed to RT and stirred for 2 h. The mixture was filteredthrough Celite washing with MeOH (80 mL) and the combined filtrate wasconcentrated in vacuo. The residue was purified by column chromatographyto give the title compound (836 mg, 73.4%) as an off white solid. LCMS(ES⁺): 201.1 [MH]⁺.

Intermediate 24 3-N-(5-Methylpyridin-2-yl)pyridine-3,4-diamine

Intermediate 24 was prepared similarly to Intermediate 23, usingIntermediate 18 instead of Intermediate 7, to give the title compound(741 mg, 70.1%) as a pale purple solid. LCMS (ES⁺): 201.1 [MH]⁺. HPLC:Rt 2.39 min, 98.5% purity.

Intermediate 25 3-N-(2,4-Difluorophenyl)pyridine-3,4-diamine

Intermediate 25 was prepared similarly to Intermediate 23, usingIntermediate 12 instead of Intermediate 7, to give the title compound(1.32 g, 73.6%) as a pink solid. LCMS (ES⁺): 222.0 [MH]⁺. HPLC: Rt 4.08min, 99.2% purity.

Intermediate 26 Methyl6-[(morpholin-4-yl)carbonyl]pyridine-3-carboxylate

5-(Methoxycarbonyl)pyridine-2-carboxylic acid (758 mg, 4.18 mmol) wasdissolved in DMF (25 mL) and morpholine (603 uL, 5.23 mmol), Et₃N (2.45mL, 16.7 mmol) and HBTU (1.67 g, 4.39 mmol) were added. The reactionmixture was stirred for 16 h and concentrated in vacuo. The residue wasdissolved in EtOAc (100 mL), washed with sat. aq. Na₂CO₃ (100 mL), dried(MgSO₄) and concentrated in vacuo. The residue was purified by columnchromatography to give the title compound (914 mg, 87.3%) as a yellowoil. LCMS (ES⁺): 251.2 [MH]⁺.

Intermediate 27 Methyl 6-(cyclopropylcarbamoyl)pyridine-3-carboxylate

Intermediate 27 was prepared similarly to Intermediate 26, usingcyclopropylamine instead of morpholine, to give the title compound (774mg, 42.4%) as a white solid. LCMS (ES⁺): 221.2 [MH]⁺.

Intermediate 28 Methyl 5-[(oxan-4-yl)amino]pyrazine-2-carboxylate

Methyl 5-chloro-2-pyrazinecarboxylate (507 mg, 2.94 mmol), Et₃N (1.08mL, 7.64 mmol) and 4-aminotetrahydropyran (395 uL, 3.82 mmol) weredissolved in dioxane (5 mL) and heated in a microwave reactor at 100° C.for 20 min. Water (50 mL) and brine (25 mL) were added and the reactionmixture was extracted into EtOAc (2×100 mL), dried (MgSO₄) andconcentrated in vacuo to give the title compound (236 mg, 33.9%) as ayellow oil. LCMS (ES⁺): 238.2 [MH]⁺.

Intermediates 29-35

Intermediates 29-35 were prepared similarly to Intermediate 28, bycoupling of with the appropriate aromatic ester with the appropriateamine; see Table 4 below.

TABLE 4 Coupling of with the appropriate aromatic ester with theappropriate amine

Form, Yield, LCMS, Int Structure Name HPLC 29

Methyl 6-(4-{[(tert- butoxy)carbonyl]amino} piperidin-1-yl)pyridine-3-carboxylate Off white solid Yield 1.66 g, 84.9% LCMS (ES⁺): 336.1 [MH]⁺HPLC: Rt 4.73 min, 98.2% purity. 30

Ethyl 2- [(cyclopropylmethyl)amino] pyrimidine-5-carboxylate Yellowsolid Yield 566 mg, 95.5% LCMS (ES⁺): 222.1 [MH]⁺ HPLC: Rt 5.79 min,92.9% purity. 31

Ethyl 2- (cyclopropylamino) pyrimidine-5-carboxylate White solid Yield526 mg, 94.7% LCMS (ES⁺): 208.1 [MH]⁺ HPLC: Rt 4.86 min, 93.7% purity.32

Methyl 5-(morpholin-4- yl)pyrazine-2-carboxylate Pale yellow solid Yield628 mg, 95.8% LCMS (ES⁺): 224.2 [MH]⁺ 33

tert-Butyl 4-[4- (methoxycarbonyl)-1,3- thiazol-2-yl]piperazine-1-carboxylate White solid Yield 324 mg, 35.1% LCMS (ES⁺): 350.1 [MNa]⁺.HPLC: Rt 6.04 min, 100% purity. 34

tert-Butyl 4-[5- (methoxycarbonyl)-1,3- oxazol-2-yl]piperazine-1-carboxylate Pale yellow solid Yield 406 mg, 42.1% LCMS (ES⁺): 334.2[MNa]⁺. HPLC: Rt 5.81 min, 97.1% purity. 35

tert-Butyl 4-[5- (methoxycarbonyl)-1,3- thiazol-2-yl]piperazine-1-carboxylate White solid Yield 712 mg, 64.4% LCMS (ES⁺): 350.2 [MNa]⁺.HPLC: Rt 6.34 min, 99.0% purity.

Intermediate 36 Methyl 6-(morpholin-4-ylmethyl)pyridine-3-carboxylate

Methyl 6-formylnicotinate (507 mg, 3.07 mmol) and morpholine (267 uL,3.07 mmol) were dissolved in DCM (20 mL) and NaBH(OAc)₃ (976 mg, 4.60mmol) was added. The reaction mixture was stirred for 2 h. The reactionmixture was diluted with DCM (40 mL) then washed with sat. aq. Na₂CO₃(40 mL), dried (MgSO₄) and the solvents removed in vacuo to yield thetitle compound (660 mg, 91.0%) as a yellow oil. LCMS (ES⁺): 237.2 [MH]⁺.

Intermediate 37 Methyl 6-(cyclopropylcarbamoyl)pyridine-3-carboxylate

Ethyl 6-aminopyridine-3-carboxylate (738 mg, 4.44 mmol) was dissolved inpyridine (20 mL), cooled to 0° C. and methanesulfonyl chloride (1.72 mL,22.2 mmol) was added. The reaction mixture was stirred at RT for 16 h,concentrated in vacuo and partitioned between DCM (50 mL) and 1M aq.citric acid (50 mL). The organic fraction was dried (MgSO₄) andconcentrated in vacuo to give the title compound (1.34 g, crude) as abrown solid. LCMS (ES⁺): 245.1 [MH]⁺.

Intermediate 38 2-[(Oxan-4-yl)amino]pyrimidine-5-carboxylic acid

2-Chloropyrimidine-5-carboxylic acid (500 mg, 3.15 mmol), Et₃N (1.15 mL,8.20 mmol) and 4-aminotetrahydropyran (335 mg, 3.31 mmol) were dissolvedin dioxane (10 mL) and heated in a microwave reactor at 150° C. for 30min. The reaction mixture was concentrated in vacuo to give the titlecompound (701 mg, crude) as a beige solid. LCMS (ES⁺): 224.1 [MH]⁺.

Intermediates 39-50

Intermediates 39-50 were prepared similarly to Intermediate 38, bycoupling of with the appropriate carboxylic acid with the appropriateamine; see Table 5 below.

TABLE 5 Coupling of with the appropriate carboxylic acid with theappropriate amine.

Form, Yield, LCMS, Int Structure Name HPLC 39

2-(3-Oxopiperazin-1- yl)pyrimidine-5-carboxylic acid Beige solid Yield701 mg, crude LCMS (ES⁺): 223.0 [MH]⁺ 40

4-Methyl-6-(morpholin-4- yl)pyridine-3-carboxylic acid Off white solidYield 401 mg, 31.0% LCMS (ES⁺): 223.1 [MH]⁺ HPLC: Rt 3.12 min, 80.5%purity 41

2-[(2R,6S)-2,6- Dimethylmorpholin-4- yl]pyrimidine-5-carboxylic acidYellow gum Yield 750 mg, 100% LCMS (ES⁺): 238.1 [MH]⁺ HPLC: Rt 4.75 min,96.5% purity 42

2-(2,2-Dimethylmorpholin- 4-yl)pyrimidine-5-carboxylic acid Yellow gumYield 224 mg, 99.8% LCMS (ES⁺): 238.1 [MH]⁺ HPLC: Rt 4.57 min, 96.2%purity 43

2-(1,4-Oxazepan-4- yl)pyrimidine-5-carboxylic acid Beige solid Yield1.50 mg, 100% LCMS (ES⁺): 224.1 [MH]⁺ 44

4-Methyl-2-(morpholin-4- yl)pyrimidine-5-carboxylic acid Yellow solidYield 540 mg, 83.5% LCMS (ES⁺): 224.1 [MH]⁺ HPLC: Rt 4.28 min, 98.2%purity 45

2-Methoxy-6-(morpholin-4- yl)pyridine-3-carboxylic acid White solidYield 151 mg, 23.8% LCMS (ES⁺): 239.1 [MH]⁺ HPLC: Rt 4.55 min, 84.0%purity 46

2-[(2-methoxyethyl)(methyl) amino]pyrimidine-5- carboxylic acid Paleorange solid Yield 752 mg, crude LCMS (ES⁺): 212.0 [MH]⁺ HPLC: Rt 4.10min, 94.9% purity 47

2-[(2- Ethoxyethyl)amino] pyrimidine-5-carboxylic acid Orange solidYield 1.34 g, crude LCMS (ES⁺): 212.1 [MH]⁺ HPLC: Rt 3.84 min, 87.0%purity 48

2-[(3- Methoxypropyl)amino] pyrimidine-5-carboxylic acid Pale yellowsolid Yield 758 mg, crude LCMS (ES⁺): 212.1 [MH]⁺ HPLC: Rt 3.67 min,97.7% purity 49

2-{[2-(Propan-2- yloxy)ethyl]amino} pyrimidine-5-carboxylic acid Orangesolid Yield 1.79 g, crude LCMS (ES⁺): 226.1 [MH]⁺ HPLC: Rt 4.25 min,98.4% purity 50

2-(4-Methyl-3- oxopiperazin-1- yl)pyrimidine-5-carboxylic acid Whitesolid Yield 1.95 g, 87.0% LCMS (ES⁺): 237.1 [MH]⁺ HPLC: Rt 3.63 min,99.8% purity

Intermediate 51 6-[(Morpholin-4-yl)carbonyl]pyridine-3-carboxylic acid

Intermediate 26 (914 mg, 3.65 mmol) was dissolved in THF/water (24 mL,1:1), lithium hydroxide monohydrate (184 mg, 4.38 mmol) was added andthe reaction mixture was stirred for 20 min. 1M aq. HCl (5 mL) was addedand the reaction mixture was extracted with EtOAc (2×100 mL), dried(MgSO₄) and concentrated in vacuo to give the title compound (633 mg,73.4%) as a white solid. LCMS (ES⁺): 237.1 [MH]⁺.

Intermediates 52-62

Intermediates 52-62 were prepared similarly to Intermediate 51, by LiOHmediated ester hydrolysis; see Table 6 below.

TABLE 6 Ester hydrolyses

Intermediate(s), Form, Int Structure Name Yield, LCMS, HPLC 52

Lithium 5-[(oxan-4- yl)amino]pyrazine-2- carboxylate From Intermediate28 Yellow solid Yield 222 mg, 100% LCMS (ES⁺): 224.1 [MH]⁺ 53

Lithium 6-(4-{[(tert-butoxy) carbonyl]amino}piperidin-1-yl)pyridine-3-carboxylate From Intermediate 29 White solid Used crudeLCMS (ES⁺): 322.1 [MH]⁺ HPLC: Rt 4.20 min, 96.8% purity 54

Lithium 2- [(cyclopropylmethyl)amino] pyrimidine-5-carboxylate FromIntermediate 30 Off white solid Used crude LCMS (ES⁺): 194.1 [MH]⁺ HPLC:Rt 4.09 min, 97.4% purity 55

Lithium 2- (cyclopropylamino) pyrimidine-5-carboxylate From Intermediate31 Off white solid Used crude LCMS (ES⁺): 180.1 [MH]⁺ HPLC: Rt 3.23 min,100% purity 56

6-(Cyclopropylcarbamoyl) pyridine-3-carboxylic acid From Intermediate 27Pink solid Yield 559 mg, 77.1% LCMS (ES⁺): 207.1 [MH]⁺ 57

6-Methanesulfonamido pyridine-3-carboxylic acid From Intermediate 37Beige solid Yield 737 mg, 76.4% LCMS (ES⁺): 217.0 [MH]⁺ 58

2-{4-[(tert-Butoxy)carbonyl] piperazin-1-yl}-1,3-thiazole- 4-carboxylicacid From Intermediate 33 White solid Yield 275 mg, 88.7% LCMS (ES⁺):336.1 [MNa]⁺ HPLC: Rt 5.12 min, 100% purity 59

2-{4-[(tert-Butoxy)carbonyl] piperazin-1-yl}-1,3-oxazole- 5-carboxylicacid From Intermediate 34 White solid Yield 324 mg, 84.4% LCMS (ES⁺):320.1 [MNa]⁺ HPLC: Rt 4.77 min, 100% purity 60

2-{4-[(tert-Butoxy)carbonyl] piperazin-1-yl}-1,3-thiazole- 5-carboxylicacid From Intermediate 35 White solid Yield 656 mg, 97.9% LCMS (ES⁺):336.1 [MNa]⁺ HPLC: Rt 5.19 min, 99.3% purity 61

Lithium 6-(morpholin-4-yl methyl)pyridine-3- carboxylate FromIntermediate 36 Yellow solid Used crude LCMS (ES⁺): 223.1 [MH]⁺ 62

Lithium 5-(morpholin-4- yl)pyrazine-2-carboxylate From Intermediate 32Yellow solid Used crude LCMS (ES⁺): 210.1 [MH]⁺

Intermediate 63 6-(3,6-Dihydro-2H-pyran-4-yl)pyridazine-3-carboxylicacid

Methyl 6-chloropyridazine-3-carboxylate (1.00 g, 5.79 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran(1.22 g, 5.79 mmol), Pd(PPh₃)₄ (536 mg, 0.464 mmol) and Cs₂CO₃ (3.40 g,10.4 mmol) were suspended in dioxane (8 mL) and water (8 mL) and heatedin a microwave reactor at 125° C. for 30 min. 1M aq. HCl (10 mL) wasadded, the precipitate was removed by filtration and the filtrate wasconcentrated in vacuo. The residue was passed through a silica padeluting with 30% MeOH in DCM and concentrated in vacuo to give the titlecompound as a white solid (946 mg, 79.2%). LCMS (ES⁺): 207.1 [MH]⁺.HPLC: Rt 3.30 min, 49.9% purity.

Intermediate 64 2-(Dimethylamino)pyrimidine-5-carbaldehyde

2-Chloropyrimidine-5-carbaldehyde (412 mg, 2.89 mmol) and Et₃N (482 uL,3.47 mmol) were dissolved in dioxane (20 mL) and a solution of Me₂NH inTHF (1.59 mL, 2.0M, 3.18 mmol) was added. The reaction mixture wasstirred for 1 h, filtered, washed with dioxane (5 mL), and concentratedin vacuo to give the title compound (427 mg, 97.7%) as a yellow solid.LCMS (ES⁺): 152.2 [MH]⁺. HPLC: Rt 4.14 min, 97.9% purity.

Intermediate 65 6-(2-Methylmorpholin-4-yl)pyridine-3-carbaldehyde

2-Chloro-5-pyridinecarboxaldehyde (500 mg, 3.53 mmol) and2-methylmorpholine (750 mg, 7.42 mmol) were dissolved in DMF (2 mL) andthe reaction mixture was heated at 100° C. in a microwave reactor for 20min and concentrated in vacuo. The residue was suspended in dioxane (5mL), filtered and concentrated in vacuo to give the title compound (730mg, 100%) as an orange gum. LCMS (ES⁺): 207.1 [MH]⁺.

Intermediate 66N-{3-[(4-Chlorophenyl)amino]pyridin-4-yl}pyridine-3-carboxamide

Intermediate 19 (234 mg, 1.07 mmol), pyridine-4-carboxylic acid (393 mg,3.20 mmol) and DIPEA (741 uL, 4.26 mmol) were dissolved in DMF (10 mL)and EDC (613 mg, 3.20 mmol) was added. The reaction mixture was stirredfor 18 h and further pyridine-3-carboxylic acid (393 mg, 3.20 mmol) andEDC (613 mg, 3.20 mmol) were added. The reaction mixture was stirred for5 h, diluted with 1M aq. Na₂CO₃ (50 mL) and extracted into DCM (3×50mL). The combined organic fractions were dried (MgSO₄) and concentratedin vacuo. The residue was purified by column chromatography to give thetitle compound as a red gum (297 mg, 85.8%). LCMS (ES⁺): 325.1 [MH]⁺.HPLC: Rt 4.08 min, 99.0% purity.

Intermediates 67-123

Intermediates 67-123 were prepared similarly to Intermediate 66, bycoupling of Intermediates 19-25 with the appropriate carboxylic acid;see Table 7 below.

TABLE 7 Amide couplings

Intermediate(s), Form, Int Structure Name Yield, LCMS, HPLC  67

N-{3-[(4- Chlorophenyl)amino]pyridin-4- yl}pyridine-4-carboxamide FromIntermediate 19 Yellow solid Yield 219 mg, 58.3% LCMS (ES⁺): 325.2[MH]⁺, HPLC: Rt 4.18 min, 95.8% purity  68

N-{3-[(4- Chlorophenyl)amino]pyridin-4- yl}-6-(morpholin-4-ylmethyl)pyridine-3- carboxamide From Intermediates 19 and 61 Yellowsolid Yield 282 mg, 21.1% LCMS (ES⁺): 424.1 [MH]⁺  69

N-{3-[(4- Chlorophenyl)amino]pyridin-4- yl}-6-(morpholin-4-yl)pyridazine-3-carboxamide From Intermediate 19 Yellow solid Yield 500mg, 58.2% LCMS (ES⁺): 411.0 [MH]⁺  70

N-{3-[(4- Chlorophenyl)amino]pyridin-4- yl}-5-(morpholin-4-yl)pyrazine-2-carboxamide From Intermediates 19 and 62 Yellow oil Yield 633 mg,73.5% LCMS (ES⁺): 411.0 [MH]⁺  71

N-{3-[(4- Chlorophenyl)amino]pyridin-4- yl}-6-[(morpholin-4-yl)carbonyl]pyridine-3- carboxamide From Intermediates 19 and 51 Yellowoil Yield 437 mg, 54.9% LCMS (ES⁺): 438.0 [MH]⁺  72

N-{3-[(4- Chlorophenyl)amino]pyridin-4- yl}-5-[(oxan-4-yl)amino]pyrazine-2- carboxamide From Intermediates 19 and 52 Yellow oilYield 174 mg, 45.6% LCMS (ES⁺): 425.1 [MH]⁺  73

tert-Butyl N-{1-[5-({3-[(4- chlorophenyl)amino]pyridin-4-yl}carbamoyl)pyridin-2- yl]piperidin-4-yl}carbamate From Intermediates19 and 53 Off white solid Yield 954 mg, 76.4% LCMS (ES⁺): 523.1 [MH]+HPLC: Rt 5.16 min, 97.8% purity  74

2-[(Cyclopropylmethyl)amino]- N-{3-[(4- fluorophenyl)amino]pyridin-4-yl}pyrimidine-5-carboxamide From Intermediates 20 and 54 Yellow solidYield 312 mg, 32.3% LCMS (ES⁺): 379.2 [MH]⁺ HPLC: Rt 4.91 min, 96.3%purity  75

2-(Cyclopropylamino)-N-{3-[(4- fluorophenyl)amino]pyridin-4-yl}pyrimidine-5-carboxamide From Intermediates 20 and 55 Yellow solidYield 659 mg, 71.2% LCMS (ES⁺): 365.1 [MH]⁺ HPLC: Rt 4.41 min, 68.3%purity  76

N-{3-[(4- Chlorophenyl)amino]pyridin-4- yl}-2-[(oxan-4-yl)amino]pyrimidine-5- carboxamide From Intermediates 19 and 38 Yellowoil Yield 917 mg, 86.3% LCMS (ES⁺): 425.1 [MH]⁺  77

N-{3-[(4- Fluorophenyl)amino]pyridin-4- yl}-2-(3-oxopiperazin-1-yl)pyrimidine-5-carboxamide From Intermediates 20 and 39 Yellow gum Usedcrude (1.88 g) LCMS (ES⁺): 408.1 [MH]⁺  78

N-{3-[(4- Chlorophenyl)amino]pyridin-4- yl}-2-(3-oxopiperazin-1-yl)pyrimidine-5-carboxamide From Intermediates 19 and 39 Yellow solidYield 712 mg, 58.8% LCMS (ES⁺): 424.1 [MH]⁺  79

5-N-{3-[(4- Chlorophenyl)amino]pyridin-4- yl}-2-N-cyclopropylpyridine-2,5-dicarboxamide From Intermediates 19 and 56 Yellow solid Yield 790mg, 84.9% LCMS (ES⁺): 408.1 [MH]⁺  80

6-(3,6-Dihydro-2H-pyran-4-yl)- N-{3-[(4- fluorophenyl)amino]pyridin-4-yl}pyridazine-3-carboxamide From Intermediates 20 and 63 Orangesemi-solid Yield 467 mg, 54.7% LCMS (ES⁺): 392.2 [MH]⁺ HPLC: Rt 4.87min,50.9% purity  81

N-{3-[(4- Chlorophenyl)amino]pyridin-4- yl}-6-methanesulfonamidopyridine- 3-carboxamide From Intermediates 19 and 57Beige solid Yield 348 mg, 40.6% LCMS (ES⁺): 418.0 [MH]⁺  82

tert-Butyl 4-[4-({3-[(4- chlorophenyl)amino]pyridin-4-yl}carbamoyl)-1,3-thiazol-2- yl]piperazine-1- carboxylate FromIntermediates 19 and 58 White solid Yield 302 mg, 66.8% LCMS (ES⁺):515.0 [MH]⁺ HPLC: Rt 6.37 min, 94.2% purity  83

tert Butyl 4-[5-({3-[(4- chlorophenyl)amino]pyridin-4-yl}carbamoyl)-1,3-oxazol-2- yl]piperazine-1-carboxylate FromIntermediates 19 and 59 Orange solid Used crude (602 mg) LCMS (ES⁺):499.0 [MH]⁺ HPLC: Rt 5.76 min, 76.4% purity  84

tert-Butyl 4-[5-({3-[(4- chlorophenyl)amino]pyridin-4-yl}carbamoyl)-1,3-thiazol-2- yl]piperazine-1-carboxylate FromIntermediates 19 and 60 Yellow solid Yield 417 mg, 39.2% LCMS (ES⁺):515.1 [MH]⁺ HPLC: Rt 5.95 min, 39.1% purity  85

N-{3-[(4- fluorophenyl)amino]pyridin-4- yl}-2-[(oxan-4-yl)amino]pyrimidine-5- carboxamide From Intermediates 20 and 38 Beigesolid Yield 593 mg, 59.0% LCMS (ES⁺): 409.1 [MH]⁺  86

N-{3-[(4- Fluorophenyl)amino]pyridin-4- yl}-4-methyl-6-(morpholin-4-yl)pyridine-3-carboxamide From Intermediates 20 and 40 Light brown oilYield 645 mg, crude LCMS (ES⁺): 408.2 [MH]⁺  87

6-Chloro-4-methyl-N-{3-[(4- methylphenyl)amino]pyridin-4-yl}pyridine-3-carboxamide From Intermediates 21 Dark oil used crude LCMS(ES⁺): 353.0 [MH]⁺  88

N-{3-[(4-Chloro-2- fluorophenyl)amino]pyridin-4-yl}-4-methyl-6-(morpholin-4- yl)pyridine-3-carboxamide FromIntermediates 22 and 40 Orange oil used crude LCMS (ES⁺): 442.1 [MH]⁺ 89

2-[(2R,6S)-2,6- Dimethylmorpholin-4-yl]-N-{3-[(4-fluorophenyl)amino]pyridin- 4-yl}pyrimidine-5-carboxamide FromIntermediates 20 and 41 Yellow gum Yield 422 mg, 79.0% LCMS (ES⁺): 423.1[MH]⁺ HPLC: Rt 5.25 min, 67.8% purity  90

2-(2,2-Dimethylmorpholin-4- yl)-N-{3-[(4- fluorophenyl)amino]pyridin-4-yl}pyrimidine-5-carboxamide From Intermediates 20 and 42 Yellow gumYield 338 mg, 84.7% LCMS (ES⁺): 423.1 [MH]⁺ HPLC: Rt 5.12 min, 75.5%purity  91

N-{3-[(4- Fluorophenyl)amino]pyridin-4- yl}-2-(1,4-oxazepan-4-yl)pyrimidine-5-carboxamide From Intermediates 20 and 43 Yellow solidYield 1.96 g, 97.7% LCMS (ES⁺): 409.2 [MH]⁺  92

N-{3-[(4- Fluorophenyl)amino]pyridin-4- yl}-4-methyl-2-(morpholin-4-yl)pyrimidine-5-carboxamide From Intermediates 20 and 44 Orange oil usedcrude LCMS (ES⁺): 409.2 [MH]⁺  93

N-{3-[(4-Chloro-2- fluorophenyl)amino]pyridin-4-yl}-4-methyl-2-(morpholin-4- yl)pyrimidine-5-carboxamide FromIntermediates 22 and 44 Orange oil used crude LCMS (ES⁺): 443.1 [MH]⁺ 94

6-Chloro-N-{3-[(4- fluorophenyl)amino]pyridin-4- yl}-2-methylpyridine-3-carboxamide From Intermediate 20 Orange oil used crude LCMS (ES⁺): 357.1[MH]⁺  95

N-{3-[(4- Fluorophenyl)amino]pyridin-4- yl}-2-methoxy-6-(morpholin-4-yl)pyridine-3-carboxamide From Intermediates 20 and 45 Yellow solidYield 119 mg, 44.3% LCMS (ES⁺): 424.1 [MH]⁺ HPLC: Rt 5.46 min, 100%purity  96

6-Chloro-N-{3-[(4- fluorophenyl)amino]pyridin-4-yl}-2,4-dimethylpyridine-3- carboxamide From Intermediate 20 used crudeLCMS (ES⁺): 371.0 [MH]⁺  97

6-Chloro-5-fluoro-N-{3-[(4- fluorophenyl)amino]pyridin-4-yl}pyridine-3-carboxamide From Intermediate 20 used crude LCMS (ES⁺):360.9 [MH]⁺  98

6-Chloro-N-{3-[(4- fluorophenyl)amino]pyridin-4-yl}-4-methoxypyridine-3- carboxamide From Intermediate 20 used crudeLCMS (ES⁺): 373.0 [MH]⁺  99

2-Chloro-N-{3-[(4- fluorophenyl)amino]pyridin-4-yl}pyridine-4-carboxamide From Intermediate 20 Yellow solid Yield 608mg, 76.6% LCMS (ES⁺): 343.1 [MH]⁺ 100

2-Cyclopropyl-N-{3-[(4- fluorophenyl)amino]pyridin-4-yl}pyrimidine-5-carboxamide From Intermediate 20 Brown gum Yield 519 mg,crude LCMS (ES⁺): 349.8 [MH]⁺ 101

2-Amino-N-{3-[(4- chlorophenyl)amino]pyridin-4-yl}pyrimidine-5-carboxamide From Intermediate 19 Orange oil used crudeLCMS (ES⁺): 340.7 [MH]⁺ 102

N-{3-[(4- Chlorophenyl)amino]pyridin-4- yl}-1-methyl-2-oxo-1,2-dihydropyridine-4- carboxamide From Intermediate 19 Orange oil usedcrude LCMS (ES⁺): 355.1 [MH]⁺ 103

N-{3-[(4- Chlorophenyl)amino]pyridin-4- yl}-1-methyl-6-oxo-1,6-dihydropyridine-3- carboxamide From Intermediate 19 Orange oil usedcrude LCMS (ES⁺): 355.1 [MH]⁺ 104

N-{3-[(4- Fluorophenyl)amino]pyridin-4- yl}-2-oxo-1,2-dihydropyridine-4-carboxamide From Intermediate 20 Orange oil used crude LCMS (ES⁺):325.1 [MH]⁺ 105

N-{3-[(4-Chloro-2- fluorophenyl)amino]pyridin-4-yl}-2-oxo-1,2-dihydropyridine- 4-carboxamide From Intermediate 22 Orangeoil used crude LCMS (ES⁺): 359.1 [MH]⁺ 106

N-{3-[(4-Chloro-2- fluorophenyl)amino]pyridin-4- yl}-6-fluoropyridine-3-carboxamide From Intermediate 22 Orange oil used crude LCMS (ES⁺): 361.1[MH]⁺ 107

2-[(2- Methoxyethyl)(methyl)amino]- N-{3-[(4-methylphenyl)amino]pyridin-4- yl}pyrimidine-5-carboxamide FromIntermediates 21 and 46 Dark oil used crude LCMS (ES⁺): 393.0 [MH]⁺ 108

6-Chloro-N-{3-[(4- fluorophenyl)amino]pyridin-4- yl}-4-methylpyridine-3-carboxamide From Intermediate 20 used crude LCMS (ES⁺): 357.3 [MH]⁺ 109

6-Fluoro-N-{3-[(4- fluorophenyl)amino]pyridin-4- yl}-4-methylpyridine-3-carboxamide From Intermediate 20 Pale yellow solid Yield 1.11 g, 66.0%LCMS (ES⁺): 341.0 [MH]⁺ 110

6-Chloro-N-{3-[(6- methylpyridin-3- yl)amino]pyridin-4-yl}pyridine-3-carboxamide From Intermediate 23 Dark oil used crude LCMS (ES⁺): 340.0[MH]⁺ 111

2-[(2R,6S)-2,6- Dimethylmorpholin-4-yl]-N-{3- [(6-methylpyridin-3-yl)amino]pyridin-4- yl}pyrimidine-5-carboxamide From Intermediates 23and 41 Dark orange oil used crude LCMS (ES⁺): 420.1 [MH]⁺ 112

6-Chloro-N-{3-[(5- methylpyridin-2- yl)amino]pyridin-4-yl}pyridine-3-carboxamide From Intermediate 24 Dark oil used crude LCMS (ES⁺): 340.0[MH]⁺ 113

N-{3-[(4- Methylphenyl)amino]pyridin-4- yl}-2-[(oxan-4-yl)amino]pyrimidine-5- carboxamide From Intermediates 21 and 38 Dark oilused crude LCMS (ES⁺): 405.0 [MH]⁺ 114

2-[(2R,6S)-2,6- Dimethylmorpholin-4-yl]-N-{3- [(5-methylpyridin-2-yl)amino]pyridin-4- yl}pyrimidine-5-carboxamide From Intermediates 24and 41 Orange oil used crude LCMS (ES⁺): 420.0 [MH]⁺ 115

2-[(3-Methoxypropyl)amino]-N- {3-[(4- methylphenyl)amino]pyridin-4-yl}pyrimidine-5-carboxamide From Intermediates 21 and 48 Dark oil usedcrude LCMS (ES⁺): 393.1 [MH]⁺ 116

N-{3-[(4- Fluorophenyl)amino]pyridin-4- yl}-2-{[2-(propan-2-yloxy)ethyl]amino}pyrimidine- 5-carboxamide From Intermediates 20 and 49Dark oil used crude LCMS (ES⁺): 411.0 [MH]⁺ 117

N-{3-[(4- Methylphenyl)amino]pyridin-4- yl}-2-{[2-(propan-2-yloxy)ethyl]amino}pyrimidine- 5-carboxamide From Intermediates 21 and 49Dark oil used crude LCMS (ES⁺): 407.1 [MH]⁺ 118

N-{3-[(4- Fluorophenyl)amino]pyridin-4- yl}-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidine- 5-carboxamide From Intermediates 20 and 50Dark oil used crude LCMS (ES⁺): 422.1 [MH]⁺ 119

N-{3-[(2,4- Difluorophenyl)amino]pyridin- 4-yl}-6-(morpholin-4-yl)pyridine-3-carboxamide From Intermediate 25 Orange oil used crudeLCMS (ES⁺): 412.0 [MH⁺ 120

2-[(2-Ethoxyethyl)amino]-N-{3- [(4-fluorophenyl)amino]pyridin-4-yl}pyrimidine-5-carboxamide From Intermediate 20 and 47 Orange oilused crude LCMS (ES⁺): 397.1 [MH]⁺ 121

2-[(2-Ethoxyethyl)amino]-N-{3- [(4- methylphenyl)amino]pyridin-4-yl}pyrimidine-5-carboxamide From Intermediate 21 and 47 Dark oil usedcrude LCMS (ES⁺): 393.1 [MH]⁺ 122

6-Fluoro-4-methyl-N-{3-[(6- methylpyridin-3-yl)amino]pyridin-4-yl}pyridine- 3-carboxamide From Intermediate 23 Darkoil used crude LCMS (ES⁺): 338.0 [MH]⁺ 123

6-Chloro-N-{3-[(4- fluorophenyl)amino]pyridin-4-yl}pyridine-3-carboxamide From Intermediate 20 Yellow solid Yield 1.06g, 63.0% LCMS (ES⁺): 342.9 [MH]⁺ HPLC: Rt 4.86 min, 91.2% purity

Intermediate 124N-{3-[(4-Fluorophenyl)amino]pyridin-4-yl}-2,4-dimethyl-6-(morpholin-4-yl)pyridine-3-carboxamide

Intermediate 96 (crude) was dissolved in NMP (2 mL) and morpholine (1.70mL, 19.7 mmol) and Et₃N (708 uL, 5.08 mmol) were added. The reactionmixture was heated at 190° C. in a microwave reactor for 30 min andpartitioned between EtOAc (50 mL) and water (50 mL). The organicfraction was washed with water (50 mL), brine (50 mL), dried (MgSO₄),concentrated in vacuo and purified by column chromatography to give thetitle compound (783 mg, 47.1%) as a yellow solid; LCMS (ES⁺): 422.0[MH]⁺, HPLC: Rt: 3.99 min, 83.2% purity.

Intermediate 125N-{3-[(4-Fluorophenyl)amino]pyridin-4-yl}-6-(oxan-4-yl)pyridazine-3-carboxamide

Intermediate 80 (220 mg, 0.562 mmol) was dissolved in MeOH (10 mL), Pd/C(cat) was added and the reaction mixture was stirred under hydrogen for2 h. The reaction mixture was filtered through Celite and concentratedin vacuo to give the crude title compound which was used withoutpurification. LCMS (ES⁺): 394.2 [MH]⁺.

Intermediate 1261-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}piperazinetrihydrochloride

Intermediate 126 was prepared similarly to Example 50, usingIntermediate 2 instead of Intermediate 1, to give the title compound(684 mg, 100%) as a white solid. LCMS (ES⁺): 375.1 [MH]⁺.

Intermediate 1272-Chloro-5-[3-(4-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridine

Intermediate 2 (1.00 g, 4.01 mmol) and 2-chloro-5-pyridinecarboxaldehyde(682 mg, 4.82 mmol) were dissolved in EtOH (8 mL) and Na₂S₂O₄ (2.79 g,16.1 mmol) was added. The reaction mixture was heated in a microwavereactor at 160° C. for 1 h, diluted with water (25 mL) and NaHCO₃ (25mL) and extracted into DCM (3×50 mL). The combined organic fractionswere dried (MgSO₄) and concentrated in vacuo. The residue was purifiedby column chromatography to give the title compound (375 mg, 28.8%) as ayellow oil. LCMS (ES⁺): 325.1 [MH]⁺.

Intermediate 1282-Chloro-5-[3-(4-chlorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridine

Intermediate 128 was prepared similarly to Intermediate 127, usingIntermediate 1 instead of Intermediate 2, to give the title compound(81.0 mg, 8.41%) as a yellow solid. LCMS (ES⁺): 341.1 [MH]⁺. HPLC: Rt:5.10 min, 97.0% purity.

Intermediate 1291-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}-1,4-diazepane

Intermediate 127 (375 mg, 1.15 mmol) and homopiperazine (578 mg, 5.77mmol) were dissolved in DMA (6 mL) and the reaction mixture was heatedin a microwave reactor at 180° C. for 30 min and concentrated in vacuo.The residue was partitioned between DCM (50 mL) and sat. aq. Na₂CO₃ (50mL) and the organic fraction dried (MgSO₄) and concentrated in vacuo togive the title compound (410 mg, 91.5%) as a red oil. LCMS (ES⁺): 389.2[MH]⁺.

Intermediates 130-133

Intermediates 130-133 were prepared similarly to Example 1, bycyclisation of Intermediates 94, 99, 104 and 108; see Table 8 below.

TABLE 8 Cyclisation of Intermediates 94, 99, 104 and 108

Intermediate(s), Form, Ex Structure Name Yield, LCMS, HPLC 130

6-Chloro-3-[3-(4-fluorophenyl)- 3H-imidazo[4,5-c]pyridin-2-yl]-2-methylpyridine From Intermediate 94 Pale brown gum Yield 123 mg, 29.5%LCMS (ES⁺): 339.1 [MH]⁺ HPLC: Rt 4.64 min, 74.0% purity 131

2-Chloro-4-[3-(4-fluorophenyl)- 3H-imidazo[4,5-c]pyridin-2- yl]pyridineFrom Intermediate 99 Yellow solid Yield 397 mg, 68.9% LCMS (ES⁺): 325.1[MH]⁺ HPLC: Rt 4.48 min, 80.2% purity 132

4-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-1,2-dihydropyridin-2-one From Intermediate 104 Pale pink solid Yield 172 mg,22.7% LCMS (ES⁺): 307.2 [MH]⁺ HPLC: Rt 3.42 min, 99.7% purity 133

2-Chloro-5-[3-(4-fluorophenyl)- 3H-imidazo[4,5-c]pyridin-2-yl]-4-methylpyridine From Intermediate 108 Yellow gum Yield 218 mg, 63.1 %LCMS (ES⁺): 338.7 [MH]⁺

Intermediate 134 1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridine

6-Azaindole (5.00 g, 42.3 mmol) was dissolved in DMF (150 mL) undernitrogen and 1-chloro-4-iodo-benzene (12.1 g, 50.8 mmol),N,N′-dimethylethylenediamine (911 uL, 8.46 mmol), K₃PO₄ (18.9 g, 88.9mmol) and CuI (806 mg, 4.23 mmol) were added. The reaction mixture washeated at 150° C. for 18 h. The reaction mixture was filtered and thefiltrate was concentrated in vacuo. The residue was suspended in 1M aq.Na₂CO₃ (250 mL) and extracted into DCM (2×250 mL). The combined organicfractions were dried (MgSO₄) and concentrated in vacuo. The residue waspurified by column chromatography to give the title compound as a yellowsolid (8.58 g, 88.6%). LCMS (ES⁺): 229.1 [MH]⁺. HPLC: Rt 4.48 min, 98.6%purity.

Intermediate 135-138

Intermediates 135-138 were prepared similarly to Intermediate 134, byarylation of 6-azaindole with the appropriate aryl or heteroaryl iodideor bromide; see Table 9 below.

TABLE 9 Arylations of 6-azaindole

Intermediate(s), Form, Ex Structure Name Yield, LCMS, HPLC 135

1-(4- Methylphenyl)- 1H-pyrrolo[2,3- c]pyridine Green gum Yield 800 mg,45.4% LCMS (ES⁺): 209.1 [MH]⁺ HPLC: Rt 4.65 min, 99.7% purity. 136

1-Phenyl-1H- pyrrolo[2,3- c]pyridine Green gum Yield 890 mg, 54.0% LCMS(ES⁺): 195.1 [MH]⁺ HPLC: Rt 4.19 min, 99.6% purity. 137

5-Methyl-2-{1H- pyrrolo[2,3- c]pyridin-1- yl}pyridine Light yellow solidYield 113 mg, 6.38% LCMS (ES⁺): 210.1 [MH]⁺ HPLC: Rt 4.45 min, 100%purity. 138

1-(4- Bromophenyl)- 1H-pyrrolo[2,3- c]pyridine Green solid Yield 1.14 g,24.7% LCMS (ES⁺): 273.0 [MH]⁺ HPLC: Rt 4.78 min, 98.5% purity.

Intermediate 139 1-[(4-Iodophenyl)carbonyl]-4-methylpiperazine

4-Iodobenzoic acid (500 mg, 2.02 mmol) and DMF (50 uL) were dissolved inDCM (24 mL), oxalyl chloride (182 uL, 2.12 mmol) was added drop-wise andthe reaction mixture was stirred for 30 min. DIPEA (421 uL, 2.42 mmol)and a solution of N-methylpiperazine (222 mg, 2.22 mmol) in DCM (1 mL)were added and the reaction mixture was stirred for 30 min, washed withsat. aq. NaHCO₃ (2×75 mL), dried (MgSO₄) and concentrated in vacuo togive the title compound (660 mg, 99.2%) as a yellow solid. LCMS (ES⁺):331.0 [MH]⁺. HPLC: Rt 4.05 min, 99.6% purity.

Intermediate 140 4-(5-Bromopyrimidin-2-yl)piperazin-2-one

5-Bromo-2-chloropyrimidine (750 mg, 3.88 mmol), DIPEA (878 uL, 5.04mmol) and piperazin-2-one (427 mg, 4.26 mmol) were dissolved in MeCN (20mL). The reaction mixture was heated at 95° C. for 1 h then allowed tocool to RT overnight. The resulting solid was collected by filtration,washed with water (2×20 mL) to give the title compound (546 mg, 54.8%)as a white solid. LCMS (ES⁺): 257.1 and 259.1 [MH]⁺. HPLC: Rt 4.68 min,98.6% purity.

Intermediate 141-142

Intermediates 141-142 were prepared similarly to Intermediate 140, bycoupling of 5-bromo-2-chloropyrimidine with the appropriate amine; seeTable 10 below.

TABLE 10 SNAr with 5-bromo-2-chloropyrimidine

Intermediate(s), Form, Ex Structure Name Yield, LCMS, HPLC 141

5-Bromo-N-(oxan-4- yl)pyrimidin-2-amine White solid Yield 645 mg, 48.4%LCMS (ES⁺): 258.0 [MH]⁺ 142

5-Bromo-N- (cyclopropylmethyl)pyrimidin- 2-amine Light yellow solidYield 476 mg, 80.7% LCMS (ES⁺): 228.1 [MH]⁺ HPLC: Rt 6.48 min, 83.9%purity.

Intermediate 143 4-(5-Bromo-4-methylpyridin-2-yl)morpholine

5-Bromo-2-fluoro-4-methylpyridine (1.00 g, 5.26 mmol) and morpholine(1.38 mL, 15.8 mmol) were dissolved in MeCN (3.0 mL) and the reactionmixture heated by microwave reactor at 140-160° C. for 1.5 h. Thereaction mixture was diluted with EtOAc (40 mL), washed with sat. aq.NaHCO₃ (40 mL), dried (MgSO₄) and the solvents removed in vacuo to givethe title compound (1.20 g, 88.7%) as a white solid. LCMS (ES⁺): 257.0[MH]⁺. HPLC: Rt 4.40 min, 95.1% purity.

Intermediate 144 1-Cyclopropyl-4-iodo-1,2-dihydropyridin-2-one

4-Iodo-1,2-dihydropyridin-2-one (1.00 g, 4.52 mmol), copper (II) acetate(879 mg, 4.84 mmol), 4,4-dipyridyl (756 mg, 4.84 mmol),cyclopropylboronic acid (875 mg, 10.2 mmol) and Na₂CO₃ (1.09 g, 10.3mmol) in DCE (40 mL) was stirred at 70° C. for 18 h. The reaction wasquenched with sat. NH₄Cl (20 mL) and water (50 mL) and extracted withDCM (2×50 mL), dried MgSO₄ and concentrated in vacuo. The crude materialwas purified by column chromatography to give the title compound (585mg, 49.5%) as a yellow oil. LCMS (ES⁺): 262.0 [MH]⁺.

Intermediate 145 4-[(5-Bromopyridin-2-yl)methyl]morpholine

5-Bromo-pyridine-2-carbaldehyde (1.00 g, 5.38 mmol) and morpholine (464uL, 5.38 mmol) were dissolved in DCM (20 mL) and NaBH(OAc)₃ (1.71 g,8.06 mmol) was added. The reaction mixture was stirred at RT for 4 dthen heated at 50° C. for 7 h. Morpholine (464 uL, 5.38 mmol) andNaBH(OAc)₃ (1.71 g, 8.06 mmol) were added and the reaction was heated at50° C. for 16 h. Water (50 mL) and sat. aq. Na₂CO₃ sol. (50 mL) wereadded and the aqueous fraction was then extracted with DCM (2×100 mL)dried (MgSO₄), filtered and the solvent removed in vacuo. The crudematerial was purified by column chromatography to give the titlecompound (1.31 g, 94.8%) as a yellow oil. LCMS (ES⁺): 257.0 [MH]⁺.

Intermediate 146 4-Iodo-1-methyl-1,2-dihydropyridin-2-one

4-Iodo-1,2-dihydropyridin-2-one (500 mg, 2.26 mmol), MeI (296 uL, 4.75mmol) and K₂CO₃ (688 mg, 4.98 mmol) were suspended in MeCN (20 mL) andstirred for 18 h. The reaction mixture was filtered and the solventsremoved in vacuo. The residue was purified by column chromatography togive the title compound (411 mg, 77.3%) as a white solid. LCMS (ES⁺):236.0 [MH]⁺. HPLC: Rt 4.48 min, 99.6% purity.

Intermediate 147 1-Ethyl-4-iodo-1,2-dihydropyridin-2-one

Intermediate 147 was prepared similarly to Intermediate 146, using ethyliodide instead of methyl iodide, to give the title compound (347 mg,61.6%) as a yellow gum. LCMS (ES⁺): 250.0 [MH]⁺. HPLC: Rt 5.04 min,96.0% purity.

Intermediate 148 6-Bromo-1-methyl-1,2-dihydropyridin-2-one

Intermediate 148 was prepared similarly to Intermediate 146, using2-bromo-6-hydroxypyridine instead of 4-iodo-1,2-dihydropyridin-2-one, togive the title compound (468 mg, 86.6%) as an off white solid. LCMS(ES⁺): 188.1 and 190.1 [MH]⁺. HPLC: Rt 4.17 min, 98.4% purity.

Example 1 3-[3-(4-Chlorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridine

Intermediate 66 (297 mg, 0.914 mmol) was dissolved in AcOH (5 mL) andheated using a microwave reactor at 100° C. for 15 min, diluted withwater (50 mL), basified with Na₂CO₃ and extracted into DCM (3×50 mL).The combined organic fractions were dried (MgSO₄) and concentrated invacuo. The residue was purified by column chromatography to give thetitle compound as a white solid (139 mg, 49.5%). HRMS (ESI⁺) calcd for[MH]⁺ of C₁₇H₁₁ClN₄ 307.0750. found 307.0748. HPLC: Rt 4.22 min, 99.8%purity.

Examples 2-43

Examples 2-43 were prepared similarly to Example 1, by cyclisation ofIntermediates 67-79, 81-86, 88-93, 95, 100-103, 105-106, 114-121, 124and 125; see Table 11 below.

TABLE 11 Cyclisation of Intermediates 67-79, 81-86, 88-93, 95, 100-103,105-106, 114-121, 124 and 125

Intermediate(s), Form, Ex Structure Name Yield, LCMS, HPLC  2

4-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2- yl]pyridine FromIntermediate 67 Light pink solid Yield 109 mg, 52.7% HRMS (ESI⁺) calcdfor [MH]⁺ of C₁₇H₁₁ClN₄ 307.0750 found 307.0752. HPLC: Rt 3.90 min,99.8% purity  3

4-({5-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2- yl]pyridin-2-yl}methyl)morpholine From Intermediate 68 White solid Yield 105 mg,38.6% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₂H₂₀ClN₅₀ 406.1435 found406.1428. HPLC: Rt 3.65 min, 100% purity  4

4-{6-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyridazin-3-yl}morpholine From Intermediate 69 White solid Yield 89.9mg, 18.8% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₇ClN₆O 393.1230 found393.1234. HPLC: Rt 4.71 min, 98.4% purity  5

4-{5-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyrazin-2-yl}morpholine From Intermediate 70 White solid Yield 114mg, 18.9% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₇ClN₆O 393.1230 found393.1234. HPLC: Rt 4.79 min, 100% purity  6

4-({5-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2- yl]pyridin-2-yl}carbonyl)morpholine From Intermediate 71 White solid Yield 170 mg,40.5% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₂H₁₈ClN₅O₂ 420.1227 found420.1228. HPLC: Rt 4.03 min, 100% purity  7

5-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-N-(oxan-4-yl)pyrazin-2-amine From Intermediate 72 Yellow solid Yield 50.0mg, 30.0% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₉ClN₆O 407.1387 found407.1380. HPLC: Rt 4.86 min, 100% purity  8

1-{5-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}piperidin-4- amine From Intermediate 73 White solidYield 24.2 mg, 38.7% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₂H₂₁ClN₆ 405.1594found 405.1591. HPLC: Rt 3.52 min, 100% purity  9

N-(Cyclopropylmethyl)-5-[3-(4- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2- amine From Intermediate 74 White solid Yield24.6 mg, 8.28% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₇FN₆ 361.1577 found361.1594. HPLC: Rt 5.01 min, 97.0% purity 10

N-Cyclopropyl-5-[3-(4- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2- amine From Intermediate 75 White solid Yield30.9 mg, 4.93% HRMS (ESI⁺) calcd for [MH]⁺ of C₁₉H₁₅FN₆ 347.1420 found347.1422. HPLC: Rt 4.46 min, 99.6% purity 11

5-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-N-(oxan-4-yl)pyrimidin-2-a mine; bis(trifluoroacetic acid) FromIntermediate 76 White solid Yield 73.8 mg, 5.39% HRMS (ESI⁺) calcd for[MH]⁺ of C₂₁H₁₉ClN₆O 407.1387 found 407.1403. HPLC: Rt 4.76 min, 100%purity 12

4-{5-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}piperazin-2- one From Intermediate 77 White solidYield 104 mg, 9.29% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₆FN₇O 390.1479found 390.1481. HPLC: Rt 4.01 min, 100% purity 13

4-{5-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}piperazin-2- one From Intermediate 78 White solidYield 97.1 mg, 14.2% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₆ClN₇O 406.1183found 406.1185. HPLC: Rt 4.25 min, 99.5% purity 14

5-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-N-cyclopropylpyridine-2- carboxamide From Intermediate 79 White solidYield 100 mg, 13.3% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₆ClN₅O 390.1122found 390.1139. HPLC: Rt 4.81 min, 100% purity 15

3-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-6-(oxan-4-yl)pyridazine From Intermediate 125 Off white solid Yield 14.0mg, 6.63% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₈FN₅O 376.1573 found376.1575. HPLC: Rt 4.37 min, 98.4% purity 16

N-{5-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2- yl]pyridin-2-yl}methanesulfonamide From Intermediate 81 White solid Yield 163 mg,48.8% HRMS (ESI⁺) calcd for [MH]⁺ of C₁₈H₁₄ClN₅O₂S 400.0635 found400.0631. HPLC: Rt 4.19 min, 100% purity 17

1-{4-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-1,3-thiazol-2-yl}piperazine dihydrochloride From Intermediate 82 Yellowsolid Yield 47.3 mg, 17.3% * HRMS (ESI⁺) calcd for [MH]⁺ of C₁₉H₁₇ClN₆S397.1002 found 397.1011. HPLC: Rt 3.44-3.55 min, 100% purity 18

1-{5-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-1,3-thiazol-2-yl}piperazine dihydrochloride From Intermediate 83 Orangesolid Yield 58.0 mg, 11.8% * HRMS (ESI⁺) calcd for [MH]⁺ of C₁₉H₁₇ClN₆O381.1230 found 381.1241. HPLC: Rt 3.25 min, 100% purity 19

1-{5-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-1,3-thiazol-2-yl}piperazine From Intermediate 84 Off white solid Yield 9.50mg, 2.96% * HRMS (ESI⁺) calcd for [MH]⁺ of C₁₉H₁₇ClN₆S 397.1002 found397.1008. HPLC: Rt 3.41-3.53 min, 99.3% purity 20

5-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-N-(oxan-4-yl)pyrimidin-2-amine From Intermediate 85 White solid Yield 79.0mg, 13.9% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₉FN₆O 391.1682 found391.1693. HPLC: Rt 4.47 min, 100% purity 21

4-{5-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-4-methylpyridin-2-yl}morpholine From Intermediate 86 White solid Yield15.2 mg, 2.17% HRMS (ESI⁺) calcd for [MH]⁺of C₂₂H₂₀FN₅O 390.1730 found390.1721. HPLC: Rt 4.09 min, 98.2% purity 22

4-{5-[3-(4-Chloro-2- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4-methylpyridin- 2-yl}morpholine From Intermediate 88Yellow solid Yield 16.0 mg, 3.59% HRMS (ESI⁺) calcd for [MH]⁺ ofC₂₂H₁₉ClFN₅O 424.1340 found 424.134. HPLC: Rt 4.31 min, 98.4% purity 23

(2R,6S)-4-{5-[3-(4- Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}- 2,6-dimethylmorpholine From Intermediate89 Beige solid Yield 25.8 mg, 6.39% HRMS (ESI⁺) calcd for [MH]⁺ ofC₂₂H₂₁FN₆O 405.1839 found 405.1843. HPLC: Rt 5.14 min, 99.1% purity 24

4-{5-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}-2,2- dimethylmorpholine From Intermediate 90 Whitesolid Yield 17.1 mg, 5.28% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₂H₂₁ FN₆O405.1839 found 405.1852. HPLC: Rt 5.14 min, 97.4% purity 25

4-{5-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}-1,4- oxazepane From Intermediate 91 White solid Yield415 mg, 43.5% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₉FN₆O 391.1682 found391.1682. HPLC: Rt 4.80 min, 98.7% purity 26

4-{5-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-4-methylpyrimidin-2- yl}morpholine From Intermediate 92 White solid Yield8.50 mg, 1.76% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₉FN₆O 391.1682 found391.1676. HPLC: Rt 4.54 min, 97.8% purity 27

4-{5-[3-(4-Chloro-2- fluorophenyl)-3H-imidazo[4,5- c]pyridin-2-yl]-4-methylpyrimidin-2- yl}morpholine From Intermediate 93 White solid Yield37.0 mg, 8.28% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₈ClFN₆O 425.1293found 425.1296. HPLC: Rt 4.92 min, 99.8% purity 28

4-{5-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-6-methoxypyridin-2- yl}morpholine From Intermediate 95 Pale yellow solidYield 47.4 mg, 41.6% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₂H₂₀FN₅O₂ 406.1679found 406.1683. HPLC: Rt 5.02 min, 99.5% purity 29

4-{5-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-4,6-dimethylpyridin-2- yl}morpholine From Intermediate 124 Off white solidYield 15.0 mg, 2.00% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₃H₂₂FN₅O 404.1887found 404.1889. HPLC: Rt 3.74 min, 99.5% purity 30

2-Cyclopropyl-5-[3-(4- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidine From Intermediate 100 Off white solid Yield50.2 mg, 17.3% HRMS (ESI⁺) calcd for [MH]⁺ of C₁₉H₁₄FN₅ 332.1311 found332.1313. HPLC: Rt 4.59 min, 99.7% purity 31

5-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2- yl]pyrimidin-2-amineFrom Intermediate 101 Off white solid Yield 14.0 mg, 3.16% HRMS (ESI⁺)calcd for [MH]⁺ of C₁₆H₁₁ClN₆ 323.0812 found 323.0815. HPLC: Rt 3.79min, 100% purity 32

4-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-1-methyl-1,2-dihydropyridin-2- one From Intermediate 102 White solid Yield109 mg, 17.7% HRMS (ESI⁺) calcd for [MH]⁺ of C₁₈H₁₃ClN₄O 337.0856 found337.0859. HPLC: Rt 4.07 min, 98.8% purity 33

5-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-1-methyl-1,2-dihydropyridin-2- one From Intermediate 103 Off white solidYield 24.0 mg, 7.83% HRMS (ESI⁺) calcd for [MH]⁺ of C₁₈H₁₃ClN₄O 337.0856found 337.0857. HPLC: Rt 4.14 min, 99.6% purity 34

4-[3-(4-Chloro-2-fluorophenyl)- 3H-imidazo[4,5-c]pyridin-2-yl]-1,2-dihydropyridin-2-one From Intermediate 105 White solid Yield 15.0mg, 1.05% HRMS (ESI) calcd for [MH]⁺ of C₁₇H₁₀ClFN₄O 341.0605 found341.0607. HPLC: Rt 3.55 min, 100% purity 35

5-[3-(4-Chloro-2-fluorophenyl)- 3H-imidazo[4,5-c]pyridin-2-yl]-1,2-dihydropyridin-2-one From Intermediate 106 White solid Yield 41.0mg, 5.72% HRMS (ESI⁺) calcd for [MH]⁺ of C₁₇H₁₀ClFN₄O 341.0605 found341.0613. HPLC: Rt 3.65 min, 100% purity 36

(2R,6S)-2,6-Dimethyl-4-{5-[3- (5-methylpyridin-2-yl)-3H-imidazo[4,5-c]pyridin-2- yl]pyrimidin-2-yl}morpholine From Intermediate114 White solid Yield 26.0 mg, 3.71% HRMS (ESI⁺) calcd for [MH]⁺ ofC₂₂H₂₃N₇O 402.2042 found 402.2047. HPLC: Rt 4.96 min, 98.8% purity 37

N-(3-Methoxypropyl)-5-[3-(4- methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2- amine From Intermediate 115 White solidYield 65.0 mg, 8.65% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₂₂N₆O 375.1933found 375.1935. HPLC: Rt 4.66 min, 99.3% purity 38

5-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-N- [2-(propan-2-yloxy)ethyl]pyrimidin-2-amine From Intermediate 116 White solid Yield181 mg, 23.4% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₂₁FN₆O 393.1839 found393.1823. HPLC: Rt 4.80 min, 99.4% purity 39

5-[3-(4-Methylphenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-N- [2-(propan-2-yloxy)ethyl]pyrimidin-2-amine From Intermediate 117 White solid Yield55.7 mg, 7.14% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₂H₂₄N₆O 389.2090 found389.2083. HPLC: Rt 5.01 min, 100% purity 40

4-{5-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}-1- methylpiperazin-2-one From Intermediate 118 Whitesolid Yield 128 mg, 21.5% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₈FN₇O404.1635 found 404.1620. HPLC: Rt 4.22 min, 100% purity 41

4-{5-[3-(2,4-Difluorophenyl)- 3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine From Intermediate 119 White solid Yield 41.1mg, 6.60% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₇F₂N₅O 394.1479 found394.1469. HPLC: Rt 4.47 min, 99.2% purity 42

N-(2-Ethoxyethyl)-5-[3-(4- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2- amine From Intermediate 120 Off white solidYield 154 mg, 27.6% LCMS (ES⁺): 379.0 [MH]⁺ HPLC: Rt 4.70 min, 99.1%purity 43

N-(2-Ethoxyethyl)-5-[3-(4- methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2- amine From Intermediate 121 White solidYield 119 mg, 21.1% LCMS (ES⁺): 375.1 [MH]⁺ HPLC: Rt 4.94 min, 99.1%purity * Boc deprotection under reaction conditions

Example 445-[3-(4-Chlorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-1H-imidazole

Intermediate 1 (200 mg, 0.753 mmol) and imidazole-4-carboxaldehyde (86.8mg, 0.903 mmol) were dissolved in EtOH (5 mL) and Na₂S₂O₄ (524 mg, 3.01mmol) was added. The reaction mixture was heated using a microwavereactor at 160° C. for 1 h, diluted with sat. aq. NaHCO₃ (25 mL) andwater (25 mL), and extracted into DCM (3×50 mL). The combined organicfractions were dried (MgSO₄) and concentrated in vacuo. The residue waspurified by column chromatography to give the title compound as a yellowsolid (51.2 mg, 23.0%). HRMS (ESI⁺) calcd for [MH]⁺ of C₁₅H₁₀ClN₅296.0703. found 296.0709. HPLC: Rt 3.24 min, 100% purity.

Examples 45-72

Examples 45-72 were prepared similarly to Example 44, by reductivecondensation of Intermediates 1-11 with the appropriate aldehyde; seeTable 12 below.

TABLE 12 Reductive condensations of Intermediates 1-11

Intermediate(s) used, Form, Yield, LCMS, Ex Structure Name HPLC 45

1-({3-[3-4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]phenyl}methyl)-4- methylpiperazine; formic acid From Intermediate 1White solid Yield 34.6 mg, 9.91% HRMS (ESI⁺) calcd for [MH]⁺ ofC₂₄H₂₄ClN₅ 418.1798 found 418.1794. HPLC: Rt 3.51 min, 99.0% purity 46

1-({4-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]phenyl}methyl)-4- methylpiperazine; formic acid From Intermediate 1Light yellow solid Yield 42.0 mg, 12.0% HRMS (ESI⁺) calcd for [MH]⁺ ofC₂₄H₂₄ClN₅ 418.1798 found 418.1813. HPLC: Rt 3.43 min, 99.1% purity 47

4-{5-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine From Intermediate 1 White solid Yield 70.9mg, 20.9% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₈ClN₅O 392.1278 found392.1282. HPLC: Rt 4.49 min, 100% purity 48

1-({4-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]phenyl}methyl)-1H- imidazole From Intermediate 1 Orange gum Yield39.4 mg, 11.4% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₂H₁₆ClN₅ 386.1172 found386.1174. HPLC: Rt 3.90 min, 100% purity 49

4-({4-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]phenyl}methyl)morpholine From Intermediate 1 Yellow solid Yield 9.81mg, 2.84% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₃H₂₁ClN₄O 405.1482 found405.1478. HPLC: Rt 3.85 min, 100% purity 50

1-{5-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}piperazine From Intermediate 1 Yellow solid Yield 3.10mg, 1.39% * HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₉ClN₆ 391.1438 found391.1427. HPLC: Rt 3.51 min, 100% purity 51

4-{5-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine From Intermediate 1 White solid 2.75 mg,0.73% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₇ClN₆O 393.1230 found393.1234. HPLC: Rt 5.06 min, 97.9% purity 52

4-{5-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine From Intermediate 2 White solid Yield 166mg, 36.6% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₇FN₆O 377.1526 found377.1514. HPLC: Rt 4.68 min, 98.1% purity 53

4-{5-[3-(2-Fluoro-4- methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2- yl}morpholine From Intermediate 3 Whitesolid Yield 40.1 mg, 13.5% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₉FN₆O391.1682 found 391.1674. HPLC: Rt 4.77 min, 99.3% purity 54

4-{5-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine From Intermediate 2 White solid Yield 42.1mg, 14.0% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₈FN₅O 376.1573 found376.1560. HPLC: Rt 4.20 min, 98.2% purity 55

4-{5-[3-(4-Fluoro-2- methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2- yl}morpholine From Intermediate 4 Paleyellow solid Yield 22.2 mg, 3.74% HRMS (ESI⁺) calcd for [MH]⁺ ofC₂₁H₁₉FN₆O 391.1682 found 391.1679. HPLC: Rt 4.67 min, 98.2% purity 56

4-{5-[3-(2-Chloro-4- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2- yl}morpholine From Intermediate 5 Off whitesolid Yield 32.4 mg, 4.97% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₆ClFN₆O411.1136 found 411.1127. HPLC: Rt 4.72 min, 100% purity 57

4-{5-[3-(4-Methylphenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine From Intermediate 6 White solid Yield 35.7mg, 5.22% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₂₀N₆O 373.1777 found373.1763. HPLC: Rt 4.80 min, 99.4% purity 58

4-{5-[3-(6-Methylpyridin-3-yl)- 3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine From Intermediate 7 Off white solid Yield39.0 mg, 5.14% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₉N₇O 374.1729 found374.1736. HPLC: Rt 3.90 min, 99.1% purity 59

4-{5-[3-(4-Bromophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine From Intermediate 8 White solid Yield 55.0mg, 7.80% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₇BrN₆O 437.0725 found437.0717. HPLC: Rt 5.15 min, 99.0% purity 60

4-{5-[3-(2-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine From Intermediate 9 White solid Yield 18.0mg, 2.38% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₇FN₆O 377.1526 found377.1515. HPLC: Rt 4.54 min, 99.4% purity 61

4-{5-[3-(2-Chloro-4- fluorophenyl)-3H-imidazol[4,5-c]pyridin-2-yl]pyridin-2- yl}morpholine From Intermediate 5 Pale yellowsolid Yield 23.0 mg, 3.54% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₇ClFN₅O410.1184 found 410.1189. HPLC: Rt 4.54 min, 99.2% purity 62

4-{5-[3-(4-Fluoro-2- methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2- yl}morpholine From Intermediate 4 Pale yellowsolid Yield 21.1 mg, 3.57% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₂H₂₀FN₅O390.1730 found 390.1723. HPLC: Rt 4.50 min, 99.3% purity 63

4-{5-[3-(4-Methylphenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine From Intermediate 6 White solid Yield 72.0mg, 9.51% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₂H₂₁N₅O 372.1824 found372.1820. HPLC: Rt 4.75 min, 100% purity 64

4-{5-[3-(6-Methylpyridin-3-yl)- 3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine From Intermediate 7 White solid Yield 52.0mg, 7.24% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₂₀N₆O 373.1777 found373.1768. HPLC: Rt 3.69 min, 100% purity 65

4-{2-[6-(Morpholin-4-yl)pyridin- 3-yl]-3H-imidazo[4,5-c]pyridin-3-yl}phenol From Intermediate 10 Off white solid Yield 106 mg, 14.0%HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₉N₅O₂ 374.1617 found 374.1618. HPLC:Rt 3.88 min, 99.5% purity 66

4-(5-{3-[4- (Trifluoromethyl)phenyl]-3H- imidazo[4,5-c]pyridin-2-yl}pyridin-2-yl)morpholine From Intermediate 11 Off white solid Yield22.0 mg, 3.09% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₂H₁₈F₃N₅O 426.1541 found426.1549. HPLC: Rt 4.88 min, 99.5% purity 67

4-{5-[3-(2-Fluoro-4- methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2- yl}morpholine From Intermediate 3 Pale yellowsolid Yield 78.3 mg, 10.6% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₂H₂₀FN₅O390.1730 found 390.1729. HPLC: Rt 4.66 min, 99.7% purity 68

4-{5-[3-(2-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine From Intermediate 9 White solid Yield 73.0mg, 9.69% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₈FN₅O 376.1573 found376.1584. HPLC: Rt 4.33 min, 99.5% purity 69

5-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-2-(pyrrolidin-1-yl)pyrimidine From Intermediate 2 White solid Yield 42.2mg, 7.29% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₇FN₆ 361.1577 found361.1584. HPLC: Rt 4.83 min, 98.5% purity 70

4-{5-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}-2- methylmorpholine From Intermediates 2 and Orangesolid Yield 42.7 mg, 9.11% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₂H₂₀FN₅O390.1730 found 390.1726. HPLC: Rt 4.54 min, 99.4% purity 71

5-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-N,N-dimethylpyridin-2-amine From Intermediate 2 White solid Yield 84.0mg, 12.6% HRMS (ESI⁺) calcd for [MH]⁺ of C₁₉H₁₆FN₅ 334.1468 found334.1475. HPLC: Rt 3.72 min, 100% purity 72

5-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-N,N-dimethylpyrimidin-2- amine From Intermediates 1 and White solidYield 12.6 mg, 1.91% HRMS (ESI⁺) calcd for [MH]⁺ of C₁₈H₁₅C1N₆ 351.1125found 351.1125. HPLC: Rt 4.90 min, 100% purity * Additional Bocdeprotection step incorporated

Example 734-{4-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine

Intermediate 20 (250 mg, 1.24 mmol),2-(morpholin-4-yl)pyridine-4-carbaldehyde (238 mg, 1.24 mmol) andNa₂S₂O₄ (646 mg, 3.71 mmol) were suspended in EtOH (2 mL) and thereaction mixture was heated at 150° C. in a microwave reactor for 45min. The reaction mixture was poured into 1M aq. Na₂CO₃ (25 mL) andextracted with DCM (2×25 mL). The combined organic fractions were dried(MgSO₄) and concentrated in vacuo. The residue was triturated from MeOH(2 mL) to give the title compound (101 mg, 21.7%) as an off white solid.HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₈FN₅O 376.1573. found 376.1573.HPLC: Rt 3.89 min, 97.8% purity.

Example 744-{5-[3-(4-Chloro-3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine

Intermediate 13 (200 mg, 0.747 mmol),2-(morpholin-4-yl)pyrimidine-5-carbaldehyde (188 mg, 0.971 mmol) andNa₂S₂O₄ (520 mg, 2.99 mmol) were suspended in EtOH (5 mL) and thereaction mixture was heated using a microwave reactor at 160° C. for 1h. The reaction mixture was diluted with 1M aq. Na₂CO₃ (40 mL) andextracted into DCM (2×50 mL). The combined organic fractions were dried(MgSO₄) and concentrated in vacuo. The residue was purified by columnchromatography and by reverse phase HPLC to give the title compound(36.6 mg, 11.9%) as an off white solid. HRMS (ESI⁺) calcd for [MH]⁺ ofC₂₀H₁₆ClFN₆O 411.1136. found 411.1133. HPLC: Rt 5.09 min, 99.7% purity.

Examples 75-84

Examples 75-84 were prepared similarly to Example 74, by reductivecondensation of Intermediates 14-18 with the appropriate aldehyde; seeTable 13 below.

TABLE 13 Reductive condensations of Intermediates 14-18

Intermediate(s) used, Form, Yield, LCMS, Ex Structure Name HPLC 75

4-{5-[3-(5-Chloropyridin-2-yl)- 3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine; tris(trifluoroacetic acid) FromIntermediate 14 White solid Yield 29.0 mg, 4.47% HRMS (ESI⁺) calcd for[MH]⁺ of C₁₉H₁₆ClN₇O 394.1183 found 394.1168. HPLC: Rt 4.68 min, 97.8%purity 76

4-{5-[3-(5-Fluoropyridin-2-yl)- 3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine From Intermediate 15 White solid Yield 53.2mg, 7.49% HRMS (ESI⁺) calcd for [MH]⁺ of C₁₉H₁₆FN₇O 378.1479 found378.1473. HPLC: Rt 4.36 min, 98.4% purity 77

4-{5-[3-(4-Chloro-2- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2- yl}morpholine From Intermediate 16 Yellowsolid Yield 186 mg, 15.4% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₆ClFN₆O411.1136 found 411.1142. HPLC: Rt 5.09 min, 97.6% purity 78

4-{5-[3-(2,4-Difluorophenyl)- 3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine From Intermediate 17 Pale yellow solidYield 39.2 mg, 4.54% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₆F₂N₆O 395.1432found 395.1436. HPLC: Rt 4.76 min, 99.6% purity 79

4-{5-[3-(5-Methylpyridin-2-yl)- 3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine From Intermediate 18 Off white solid Yield46.1 mg, 9.47% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₉N₇O 374.1729 found374.1736. HPLC: Rt 4.30 min, 99.6% purity 80

4-{5-[3-(4-Chloro-2- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2- yl}morpholine From Intermediate 16 White solidYield 41.0 mg, 12.8% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₇ClFN₅O410.1184 found 410.1187. HPLC: Rt 4.58 min, 99.6% purity 81

4-{5-[3-(5-Chloropyridin-2-yl)- 3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine From Intermediate 14 White solid Yield 7.05mg, 2.57% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₇ClN₆O 393.1230 found393.1226. HPLC: Rt 4.45 min, 97.9% purity 82

4-{5-[3-(5-Methylpyridin-2-yl)- 3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine From Intermediate 18 White solid Yield 38.0mg, 7.83% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₂₀N₆O 373.1777 found373.1787. HPLC: Rt 4.03 min, 99.4% purity 83

5-[3-(4-Chloro-2-fluorophenyl)- 3H-imidazo[4,5-c]pyridin-2-yl]-2-(pyrrolidin-1-yl)pyrimidine From Intermediate 16 White solid Yield8.20 mg, 2.22% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₆ClFN₆ 395.1187 found395.1190. HPLC: Rt 5.09 min, 100% purity 84

5-[3-(4-Chloro-2-fluorophenyl)- 3H-imidazo[4,5-c]pyridin-2-yl]-N,N-dimethylpyrimidin-2- amine From Intermediates 16 and 64 Light yellowsolid Yield 63.7 mg, 13.6% HRMS (ESI⁺) calcd for [MH]⁺ of C₁₈H₁₄ClFN₆369.1031 found 369.1031. HPLC: Rt 4.93 min, 100% purity

Example 85N-(1-{5-[3-(4-Chlorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}piperidin-4-yl)acetamide

Example 8 (100 mg, 0.247 mmol), Et₃N (41.2 uL, 0.296 mmol) and acetylchloride (19.3 uL, 0.272 mmol) were dissolved in DCM (10 mL) and thereaction mixture was stirred for 2 h and concentrated in vacuo. Theresidue was purified by column chromatography and partitioned betweenDCM (20 mL) and sat. aq. NaHCO₃ (20 mL). The organic fraction was washedwith sat. aq. NaHCO₃ (20 mL), dried (MgSO₄) and concentrated in vacuo togive the title compound (61.6 mg, 55.8%) as a light yellow solid. HRMS(ESI⁺) calcd for [MH]⁺ of C₂₄H₂₃ClN₆O 447.1700. found 447.1701. HPLC: Rt3.98 min, 99.7% purity.

Example 861-(4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}piperazin-1-yl)ethan-1-one

Example 86 was prepared similarly to Example 85, using Intermediate 126instead of Example 8, to give the title compound (227 mg, 38.7%) as awhite solid. HRMS (ESI⁺) calcd for [MH]⁺ of C₂₃H₂₁FN₆O 417.1839. found417.1851. HPLC: Rt 4.26 min, 100% purity.

Example 871-(4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}-1,4-diazepan-1-yl)ethan-1-one;bis(trifluoroacetic acid)

Example 87 was prepared similarly to Example 85, using Intermediate 129instead of Example 8, to give the title compound (143 mg, 41.2%) as apink gum. HRMS (ESI⁺) calcd for [MH]⁺ of C₂₄H₂₃FN₆O 431.1996. found431.1997. HPLC: Rt 4.41 min, 99.7% purity.

Example 88N-(1-{5-[3-(4-Chlorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}piperidin-4-yl)methanesulfonamide

Example 8 (100 mg, 0.247 mmol), Et₃N (41.2 uL, 0.296 mmol) andmethanesulfonyl chloride (26.8 uL, 0.346 mmol) were dissolved in DCM (10mL) and the reaction mixture was stirred for 2 h, diluted with DCM (20mL), washed with sat. aq. NaHCO₃ (30 mL), dried (MgSO₄) and concentratedin vacuo. The residue was triturated from MeOH (3 mL) and collected byfiltration to give the title compound (30.6 mg, 25.7%) as a yellowsolid. HRMS (ESI⁺) calcd for [MH]⁺ of C₂₃H₂₃ClN₆O₂S 483.1370. found483.1375. HPLC: Rt 4.18 min, 99.4% purity.

Example 891-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}-4-methanesulfonylpiperazine

Example 89 was prepared similarly to Example 88, using Intermediate 126instead of Example 8, to give the title compound (44.5 mg, 10.3%) as ayellow solid. HRMS (ESI⁺) calcd for [MH]⁺ of C₂₂H₂₁FN₆O₂S 453.1509.found 453.1522. HPLC: Rt 4.59 min, 98.2% purity.

Example 904-{5-[3-(4-Chlorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}piperazine-1-carboxamidedihydrochloride

Example 50 trihydrochloride (94.5 mg, 0.189 mmol) was dissolved in DCM(5 mL), and DIPEA (145 uL, 0.831 mmol) and trimethylsilyl isocyanate(30.7 uL, 0.227 mmol) were added. The reaction mixture was stirred for16 h, diluted with 1M aq. Na₂CO₃ (25 mL) and extracted into DCM (3×25mL). The combined organic fractions were dried (MgSO₄) and concentratedin vacuo. The residue was dissolved in 1.25M HCl in EtOH (5 mL), stirredfor 1 h and concentrated in vacuo. The residue was purified by reversephase HPLC to give the title compound (21.4 mg, 22.3%) as a yellowsolid. HRMS (ESI⁺) calcd for [MH]⁺ of C₂₂H₂₀ClN₇O 434.1496. found434.1497. HPLC: Rt 4.19 min, 98.5% purity.

Examples 91-94

Examples 91-94 were prepared similarly to Example 90, by reaction ofExamples 8, 18 and Intermediates 126, 129 with trimethylsilylisocyanate; see Table 14 below.

TABLE 14 Reaction of Examples 8, 18 and Intermediates 126, 129 withtrimethylsilyl isocyanate

Intermediate(s) used, Form, Yield, LCMS, Ex Structure Name HPLC 91

(1-{5-[3-(4- Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}piperidin- 4-yl)urea; bis(trifluoroacetic acid) FromExample 8 Yellow solid Yield 36.3 mg, 21.7% HRMS (ESI⁺) calcd for [MH]⁺of C₂₃H₂₂ClN₇O 448.1653 found 448.1656. HPLC: Rt 3.75 min, 98.7% purity92

4-{5-[3-(4- Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2- yl]pyridin-2-yl}piperazine-1- carboxamide From Intermediate 126 White solid Yield44.0 mg, 11.1% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₂H₂₀FN₇O 418.1791 found418.1795. HPLC: Rt 3.88 min, 100% purity 93

4-{5-[3-(4- Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2- yl]-1,3-oxazol-2-yl}piperazine-1- carboxamide From Example 18 Pale yellow solid Yield7.20 mg, 7.71% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₈ClN₇O₂ 424.1289found 424.1288. HPLC: Rt 4.20 min, 99.7% purity 94

4-{5-[3-(4- Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}-1,4- diazepane-1- carboxamide From Intermediate 129Pink solid Yield 56.7 mg, 24.9% HRMS (ESI⁺) calcd for [MH]⁺ ofC₂₃H₂₂FN₇O 432.1948 found 432.1955. HPLC: Rt 3.83 min, 99.0% purity

Example 954-(5-{3-Phenyl-3H-imidazo[4,5-c]pyridin-2-yl}pyrimidin-2-yl)morpholine

Example 51 (115 mg, 0.293 mmol) was suspended in EtOH (5 mL) andammonium formate (148 mg, 2.34 mmol) and 10% Pd/C (50.0 mg) were added.The reaction mixture was heated under reflux for 5 h, filtered throughCelite and concentrated in vacuo. The residue was dissolved in DCM (50mL), washed with 1M aq. Na₂CO₃ (50 mL) dried (MgSO₄) and concentrated invacuo. The residue was purified by column chromatography to give thetitle compound (40.2 mg, 38.3%) as a white solid. HRMS (ESI⁺) calcd for[MH]⁺ of C₂₀H₁₈N₆O 359.1620. found 359.1613. HPLC: Rt 4.65 min, 99.8%purity.

Example 964-{5-[3-(4-Cyclopropylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine

Example 51 (250 mg, 0.636 mmol), cyclopropylboronic acid (54.7 mg, 0.636mmol), Pd(OAc)₂ (14.3 mg, 63.6 umol), XPhos (30.3 mg, 63.6 umol) andCs₂CO₃ (518 mg, 1.59 mmol) were dissolved in dioxane (1.5 mL) and water(1.5 mL) and heated in a sealed tube at 100° C. for 16 h. The reactionmixture was partitioned between DCM (20 mL) and water (20 mL) and theorganic fraction was washed with brine (20 mL), dried (MgSO₄) andconcentrated in vacuo. The residue was purified by reverse phase HPLC togive the title compound (17.1 mg, 6.74%) as a white solid. HRMS (ESI⁺)calcd for [MH]⁺ of C₂₃H₂₂N₆O 399.1933. found 399.1938. HPLC: Rt 5.16min, 99.4% purity.

Example 974-{4-Methyl-5-[3-(4-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine

Intermediate 87 (300 mg, 1.51 mmol) was dissolved in NMP (2 mL) andmorpholine (783 uL, 9.08 mmol) and the reaction mixture was heated at180° C. in a microwave reactor for 30 min. The reaction mixture wasdiluted with EtOAc (10 mL) and water (10 mL). The organic fraction waswashed with brine (10 mL), dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by reverse phase HPLC to give the title compound(16.4 mg, 2.81%) as a colourless gum. HRMS (ESI⁺) calcd for [MH]⁺ ofC₂₃H₂₃N₅O 386.1981. found 386.1982. HPLC: Rt 4.17 min, 99.3% purity.

Examples 98-107

Examples 98-107 were prepared similarly to Example 97, by SnAr andcyclisation of Intermediates 97-98, 106, 109-110, 112, 122 and 123 withthe appropriate amine; see Table 15 below.

TABLE 15 SnAr and cyclisation of Intermediates 97-98, 106, 109-110, 112,122 and 123

Intermediate(s) used, Form, Yield, LCMS, Ex Structure Name HPLC  98

4-{3-Fluoro-5-[3-(4- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2- yl}morpholine From Intermediate 97 White solidYield 134 mg, 27.7% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₇F₂N₅O 394.1479found 394.1478. HPLC: Rt 4.80 min, 99.6% purity  99

5-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-2-(morpholin-4-yl)-1,4- dihydropyridin-4-one From Intermediate 98 Whitesolid Yield 15.0 mg, 1.11% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₈FN₅O₂392.1523 found 392.1520. HPLC: Rt 3.73 min, 100% purity 100

5-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-4-methyl-N-(oxan-4-yl)pyridin-2- amine From Intermediate 109 White solidYield 26.0 mg, 8.77% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₃H₂₂FN₅O 404.1887found 404.1892. HPLC: Rt 3.56 min, 100% purity 101

N-(Cyclopropylmethyl)-5-[3-(4- fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4-methylpyridin- 2-amine From Intermediate 109 Whitesolid Yield 43.0 mg, 15.7% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₂H₂₀FN₅374.1781 found 374.1787. HPLC: Rt 3.90 min, 100% purity 102

5-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-4-methyl-2-(1H-pyrazol-1- yl)pyridine From Intermediate 109 Off whitesolid Yield 28.1 mg, 12.9% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₅FN₆371.1420 found 371.1419. HPLC: Rt 4.98 min, 99.8% purity 103

(2R,6S)-2,6-Dimethyl-4-{5-[3- (6-methylpyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2- yl]pyridin-2-yl}morpholine;tris(trifluoroacetic acid) From Intermediate 110 Yellow gum Yield 26.0mg, 1.75% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₃H₂₄N₆O 401.2090 found401.2084. HPLC: Rt 4.27 min, 99.1% purity 104

(2R,6S)-2,6-Dimethyl-4-{5-[3- (5-methylpyridin-2-yl)-3H-imidazo[4,5-c]pyridin-2- yl]pyridin-2-yl}morpholine From Intermediate112 White solid Yield 26.0 mg, 3.71% HRMS (ESI⁺) calcd for [MH]⁺ ofC₂₃H₂₄N₆O 401.2090 found 401.2098. HPLC: Rt 4.66 min, 98.9% purity 105

5-[3-(4-Chloro-2-fluorophenyl)- 3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-amine From Intermediate 106 Pale pink solid Yield 24.0 mg,8.49% HRMS (ESI⁺) calcd for [MH]⁺ of C₁₇H₁₁ClFN₅ 340.0765 found340.0773. HPLC: Rt 3.30 min, 100% purity 106

4-{5-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}-1- methylpiperazin-2-one From Intermediate 123 Paleyellow solid Yield 38.5 mg, 13.1% HRMS (ESI⁺) calcd for [MH]⁺ ofC₂₂H₁₉FN₆O 403.1682 found 403.1684. HPLC: Rt 4.07 min, 99.4% purity 107

4-{4-Methyl-5-[3-(6- methylpyridin-3-yl)-3H- imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine From Intermediate 122 Pale yellow gum Yield24.0 mg, 3.11% LCMS (ES⁺): 387.0 [MH]⁺ HPLC: Rt 3.74 min, 98.7% purity

Example 1084-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-6-methylpyridin-2-yl}morpholine

Intermediate 130 (94.0 mg, 0.277 mmol) was dissolved in DMA (1 mL) andmorpholine (192 uL, 2.22 mmol) was added. The reaction mixture washeated at 200° C. in a microwave reactor for 30 min and partitionedbetween DCM (20 mL) and water (20 mL). The organic fraction was washedwith water (20 mL), dried (MgSO₄) and concentrated in vacuo. The residuewas purified by reverse phase HPLC to give the title compound (47.0 mg,43.5%) as a white solid. HRMS (ESI⁺) calcd for [MH]⁺ of C₂₂H₂₀FN₅O390.1730. found 390.1737. HPLC: Rt 3.96 min, 99.7% purity.

Examples 109-111

Examples 109-111 were prepared similarly to Example 108, by reaction ofIntermediates 128, 131 and 133 with the appropriate amine; see Table 16below.

TABLE 16 SNAr of Intermediates 128, 131 and 133 with the appropriateamine

Intermediate(s) used, Form, Yield, LCMS, Ex Structure Name HPLC 109

4-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-N,N-dimethylpyridin-2-amine From Intermediate 131 Yellow solid Yield 110 mg,53.4% HRMS (ESI⁺) calcd for [MH]⁺ of C₁₉H₁₆FN₅ 334.1468 found 334.1476.HPLC: Rt 3.19 min, 99.7% purity 110

5-[3-(4-Chlorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]pyridin- 2-amineFrom Intermediate 128 White solid Yield 20.0 mg, 26.2% HRMS (ESI⁺) calcdfor [MH]⁺ of C₁₇H₁₂ClN₅ 322.0859 found 322.0849. HPLC: Rt 3.45 min,99.7% purity 111

5-[3-(4-Fluorophenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-N,N,4-trimethylpyridin-2-amine From Intermediate 133 Light yellow solid Yield24.8 mg, 29.2% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₈FN₅ 348.1624 found348.1631. HPLC: Rt 3.44 min, 99.1% purity

Example 1125-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-2-(oxolan-3-yloxy)pyridine

NaH (14.8 mg, 60% in mineral oil, 0.370 mmol) was suspended in THF (1mL), 3-hydroxytetrahydrofuran (29.7 uL, 0.370 mmol) was added and thereaction mixture was stirred for 5 min. Intermediate 127 (80.0 mg, 0.246mmol) was added and the reaction mixture was stirred for 16 h, quenchedwith water (20 mL) and diluted with EtOAc (20 mL). The organic fractionwas washed with brine (20 mL), dried (MgSO₄) and concentrated in vacuo.The residue was purified by reverse phase HPLC to give the titlecompound (19.2 mg, 20.7%) as a white solid. HRMS (ESI⁺) calcd for [MH]⁺of C₂₁H₁₇FN₄O₂ 377.1414. found 377.1419. HPLC: Rt: 4.78 min, 98.9%purity.

Example 1135-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-2-(oxan-4-yloxy)pyridine

Example 113 was prepared similarly to Example 112, using4-hydroxytetrahydropyran instead of 3-hydroxytetrahydrofuran, to givethe title compound (20.0 mg, 20.8%) as a white solid. HRMS (ESI⁺) calcdfor [MH]⁺ of C₂₂H₁₉FN₄O₂ 391.1570. found 391.1566. HPLC: Rt 5.04 min,99.7% purity.

Example 1144-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-1-methyl-1,2-dihydropyridin-2-one

Intermediate 132 (26.0 mg, 84.9 umol) and Cs₂CO₃ (55.3 mg, 0.170 mmol)were dissolved in dioxane (0.5 mL), MeI (10.6 uL, 0.170 mmol) was addedand the reaction mixture was stirred for 16 h, filtered and concentratedin vacuo. The residue was purified by reverse phase HPLC to give thetitle compound (1.41 mg, 5.19%) as a white solid. HRMS (ESI⁺) calcd for[MH]⁺ of C₁₈H₁₃FN₄O 321.1151. found 321.1156. HPLC: Rt 3.45 min, 98.9%purity.

Example 1151-Cyclopropyl-4-[3-(4-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-1,2-dihydropyridin-2-one

Intermediate 132 (120 mg, 0.392 mmol), cyclopropylboronic acid (101 mg,1.18 mmol), Cu(OAc)₂ (110 mg, 0.607 mmol), 4,4′-dimethyl-2,2′-bipyridine(72.2 mg, 0.392 mmol) and Cs₂CO₃ (268 mg, 0.823 mmol) were suspended indioxane (2.5 mL) and the reaction mixture was stirred at 70° C. for 6 h.The reaction mixture was partitioned between EtOAc (25 mL) and water (25mL) and the organic fraction was washed with brine (25 mL), dried(MgSO₄) and concentrated in vacuo. The residue was purified by reversephase HPLC to give the title compound (22.4 mg, 16.5%) as an off whitesolid. HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₅FN₄O 347.1308. found347.1309. HPLC: Rt 3.88 min, 100% purity.

Example 1164-[3-(4-Chloro-2-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-1-cyclopropyl-1,2-dihydropyridin-2-one

Example 116 was prepared similarly to Example 115, using Example 34instead of Intermediate 132, to give the title compound (31.0 mg, 34.7%)as an off white solid. HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₄ClFN₄O381.0918. found 381.0922. HPLC: Rt 4.13 min, 100% purity.

Example 117N-(2-Methoxyethyl)-N-methyl-5-[3-(4-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-amine

Intermediate 107 (crude) was dissolved in NMP (2 mL), Et₃N (633 uL, 4.54mmol) was added and the reaction mixture was heated at 180° C. in amicrowave reactor for 30 min. The reaction mixture was partitionedbetween DCM (15 mL) and water (15 mL) and the organic fraction waswashed with brine (15 mL), dried (MgSO₄) and concentrated in vacuo. Theresidue was triturated from MeOH to give the title compound as an offwhite solid (60.3 mg, 10.6%). HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₂₂N₆O375.1933. found 375.1942. HPLC: Rt: 4.99 min, 99.3% purity.

Examples 118-119

Examples 118-119 were prepared similarly to Example 117, by cyclisationof Intermediates 111 and 113; see Table 17 below.

TABLE 17 Cyclisation of Intermediates 111 and 113

Intermediate(s) used, Form, Yield, LCMS, Ex Structure Name HPLC 118

(2R,6S)-2,6-Dimethyl-4-{5-[3- (6-methylpyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2- yl]pyrimidin-2-yl}morpholine From Intermediate111 White solid Yield 58.0 mg, 7.23% HRMS (ESI⁺) calcd for [MH]⁺ ofC₂₂H₂₃N₇O 402.2042 found 402.2046. HPLC: Rt 4.52 min, 97.6% purity 119

5-[3-(4-Methylphenyl)-3H- imidazo[4,5-c]pyridin-2-yl]-N-(oxan-4-yl)pyrimidin-2-amine; bis(trifluoroacetic acid) FromIntermediate 113 White solid Yield 12.0 mg, 1.55% HRMS (ESI⁺) calcd for[MH]⁺ of C₂₂H₂₂N₆O 387.1933 found 387.1936. HPLC: Rt 4.42 min, 99.4%purity

Example 120 4-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyridine

Intermediate 134 (100 mg, 0.437 mmol) and triisopropyl borate (212 uL,0.918 mmol) were dissolved in THF (5 mL) and the reaction mixture wascooled to 0° C. LDA (435 uL, 2.0M in THF/heptane, 0.875 mmol) was addedand the reaction mixture was stirred at 0° C. for 30 min. The reactionwas quenched with water (2 mL) and diluted with dioxane (3 mL).4-Iodopyridine (108 mg, 0.525 mmol), Pd(PPh₃)₄ (40.4 mg, 35.0 umol) anda solution of Na₂CO₃ (139 mg, 1.31 mmol) in water (4 mL) were added. Thereaction mixture was heated using a microwave reactor at 160° C. for 20min. The reaction mixture was partitioned between water (40 mL) andEtOAc (40 mL), and the organic fraction was dried (MgSO₄) andconcentrated in vacuo. The residue was purified by reverse phase HPLC togive the title compound as a light yellow solid (21.8 mg, 16.3%). HRMS(ESI⁺) calcd for [MH]⁺ of C₁₈H₁₂ClN₃ 306.0798. found 306.0809. HPLC: Rt3.52 min, 99.9% purity.

Examples 121-154

Examples 121-154 were prepared similarly to Example 120, by borateformation and Suzuki reaction of Intermediates 134-138 with theappropriate aryl or heteroaryl iodide or bromide; see Table 18 below.

TABLE 18 Borate formation and Suzuki reactions of Intermediates 134-138

Intermediate(s), Form, Ex Structure Name Yield, LCMS, HPLC 121

2-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2- yl]pyridine FromIntermediate 134 Yellow gum Yield 14.0 mg, 6.98% HRMS (ESI⁺) calcd for[MH]⁺ of C₁₈H₁₂ClN₃ 306.0798 found 306.0811. HPLC: Rt 4.82 min, 99.1%purity 122

3-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2- yl]pyridine FromIntermediate 134 Yellow gum Yield 13.1 mg, 9.80% HRMS (ESI⁺) calcd for[MH]⁺ of C₁₈H₁₂ClN₃ 306.0798 found 306.0810. HPLC: Rt 3.95 min, 99.1%purity 123

5-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2- yl]pyridine FromIntermediate 134 White solid Yield 64.9 mg, 32.2% HRMS (ESI⁺) calcd for[MH]⁺ of C₁₇H₁₁ClN₄ 307.0750 found 307.0753. HPLC: Rt 4.24 min, 99.1%purity 124

2-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2- yl]pyrazine FromIntermediate 134 Yellow gum Yield 28.0 mg, 13.9% HRMS (ESI⁺) calcd for[MH]⁺ of C₁₇H₁₁ClN₄ 307.0750 found 307.0764. HPLC: Rt 4.53 min, 99.7%purity 125

1-({4-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]phenyl}carbonyl)-4- methylpiperazine From Intermediate 134 and 139Yellow solid Yield 23.0 mg, 8.14% HRMS (ESI⁺) calcd for [MH]⁺ ofC₂₅H₂₃ClN₄O 431.1638 found 431.1638. HPLC: Rt 3.77 min, 97.9% purity 126

5-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]-2,4-dimethyl-1H-imidazole From Intermediate 134 Off white solid Yield 14.6mg, 6.90% HRMS (ESI⁺) calcd for [MH]⁺ of C₁₈H₁₅ClN₄ 323.1063 found323.1067. HPLC: Rt 3.45 min, 100% purity 127

4-{5-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine From Intermediate 134 Yellow solid Yield67.2 mg, 19.6% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₈ClN₅O 392.1278 found392.1286. HPLC: Rt 5.12 min, 100% purity 128

4-{5-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}piperazin-2- one From Intermediate 134 and 140 Whitesolid Yield 71.5 mg, 16.1% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₇ClN₆O405.1230 found 405.1226. HPLC: Rt 4.23 min, 98.6% purity. 129

4-{5-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]-4-methylpyridin-2-yl}morpholine; bis(trifluoroacetic acid) FromIntermediate 134 and 143 Colourless gum Yield 6.55 mg, 0.95% HRMS (ESI⁺)calcd for [MH]⁺ of C₂₃H₂₁ClN₄O 405.1482 found 405.1494. HPLC: Rt 4.06min, 98.6% purity. 130

4-{5-[1-(4-Methylphenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine From Intermediate 135 White solid Yield80.0 mg, 17.9% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₂H₂₁N₅O 372.1824 found372.1828. HPLC: Rt 5.21 min, 100% purity. 131

4-(5-{1-Phenyl-1H-pyrrolo[2,3- c]pyridin-2-yl}pyrimidin-2- yl)morpholineFrom Intermediate 136 White solid Yield 58.5 mg, 12.7% HRMS (ESI⁺) calcdfor [MH]⁺ of C₂₁H₁₉N₅O 358.1668 found 358.1685. HPLC: Rt 4.90 min, 97.4%purity. 132

4-{5-[1-(5-Methylpyridin-2-yl)- 1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine; tris(trifluoroacetic acid) FromIntermediate 137 Yellow solid Yield 3.35 mg, 0.87% HRMS (ESI⁺) calcd for[MH]⁺ of C₂₁H₂₀N₆O 373.1777 found 373.1794. HPLC: Rt 4.68 min, 99.6%purity. 133

4-{5-[1-(4-Bromophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine From Intermediate 138 Light yellow solidYield 38.0 mg, 9.52% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₁H₁₈BrN₅O 436.0773found 436.0773. HPLC: Rt 5.32 min, 96.2% purity. 134

5-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]-1-methyl-1H-pyrazole From Intermediate 134 Orange solid Yield 133 mg,32.8% HRMS (ESI⁺) calcd for [MH]⁺ of C₁₇H₁₃ClN₄ 309.0907 found 309.0918.HPLC: Rt 4.64 min, 98.4% purity. 135

4-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]-1-methyl-1H-pyrazole From Intermediate 134 Orange solid Yield 153 mg,37.9% HRMS (ESI⁺) calcd for [MH]⁺ of C₁₇H₁₃ClN₄ 309.0907 found 309.0910.HPLC: Rt 4.87 min, 99.5% purity. 136

5-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]-1-methyl-1H-imidazole From Intermediate 134 White solid Yield 63.8 mg,15.8% HRMS (ESI⁺) calcd for [MH]⁺ of C₁₇H₁₃ClN₄ 309.0907 found 309.0914.HPLC: Rt 3.43 min, 100% purity. 137

5-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]-N,N-dimethylpyrimidin-2-amine; bis(trifluoroacetic acid) From Intermediate134 Yellow gum Yield 142 mg, 18.7% HRMS (ESI⁺) calcd for [MH]⁺ ofC₁₉H₁₆ClN₅ 350.1172 found 350.1180. HPLC: Rt 5.46 min, 100% purity. 138

4-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]-1-cyclopropyl-1,2-dihydropyridin- 2-one From Intermediate 134 and 144Yellow solid Yield 234 mg, 36.9% HRMS (ESI⁺) calcd for [MH]⁺ ofC₂₁H₁₆ClN₃O 362.1060 found 362.1063. HPLC: Rt 4.76 min, 99.0% purity.139

5-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]-N-(oxan-4-yl)pyrimidin-2-amine From Intermediate 134 and 141 White solidYield 122 mg, 22.8% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₂H₂₀ClN₅O 406.1435found 406.1435. HPLC: Rt 4.78 min, 99.3% purity. 140

4-({5-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2- yl]pyridin-2-yl}methyl)morpholine From Intermediate 134 and 145 Beige solid Yield29.7 mg, 4.20% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₃H₂₁ClN₄O 405.1482 found405.1485. HPLC: Rt 3.91 min, 98.0% purity. 141

5-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]-4-methylpyridin-2-amine; bis(trifluoroacetic acid) From Intermediate 134Colourless gum Yield 1.68 mg, 0.34% LCMS (ES⁺): 335.1 [MH]⁺ HPLC: Rt3.63 min, 96.8% purity. 142

4-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]-1,2-dihydropyridin-2-one From Intermediate 134 Off white solid Yield 52.0mg, 14.8% HRMS (ESI⁺) calcd for [MH]⁺ of C₁₈H₁₂ClN₃O 322.0747 found322.0753. HPLC: Rt 3.75 min, 97.6% purity. 143

4-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]-1-methyl-1,2-dihydropyridin-2- one From Intermediate 134 and 146 Off whitesolid Yield 56.9 mg, 15.5% HRMS (ESI⁺) calcd for [MH]⁺ of C₁₉H₁₄ClN₃O336.0904 found 336.0909. HPLC: Rt 4.07 min, 98.6% purity. 144

4-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]-1-ethyl-1,2-dihydropyridin-2-one From Intermediate 134 and 147 Off whitesolid Yield 59.5 mg, 15.6% HRMS (ESI⁺) calcd for [MH]⁺ of C₂₀H₁₆ClN₃O350.1060 found 350.1065. HPLC: Rt 4.39 min, 100% purity. 145

6-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]-1-methyl-1,2-dihydropyridin-2- one From Intermediate 134 and 148 Whitesolid Yield 82.2 mg, 16.0% HRMS (ESI⁺) calcd for [MH]⁺ of C₁₉H₁₄ClN₃O336.0904 found 336.0914. HPLC: Rt 4.20 min, 99.5% purity. 146

5-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]-2,3-dihydropyridazin-3-one From Intermediate 134 Yellow solid Yield 35.5 mg,10.1% HRMS (ESI⁺) calcd for [MH]⁺ of C₁₇H₁₁ClN₄O 323.0699 found323.0700. HPLC: Rt 3.86 min, 98.4% purity. 147

4-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2- yl]pyridin-2-amineFrom Intermediate 134 Off white solid Yield 103 mg, 29.4% HRMS (ESI⁺)calcd for [MH]⁺ of C₁₈H₁₃ClN₄ 321.0907 found 321.0901. HPLC: Rt 3.56min, 100% purity. 148

3-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]-5- fluoropyridineFrom Intermediate 134 Yellow solid Yield 21.2 mg, 6.00% HRMS (ESI⁺)calcd for [MH]⁺ of C₁₈H₁₁ClFN₃ 324.0704 found 324.0714. HPLC: Rt 4.87min, 100% purity. 149

5-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]-N-(cyclopropylmethyl)pyrimidin- 2-amine From Intermediate 134 and 142 Offwhite solid Yield 32.0 mg, 7.79% HRMS (ESI⁺) calcd for [MH]⁺ ofC₂₁H₁₈ClN₅ 376.1329 found 376.1326. HPLC: Rt 5.38 min, 99.1% purity. 150

3-Chloro-5-[1-(4- chlorophenyl)-1H-pyrrolo[2,3- c]pyridin-2-yl]pyridineFrom Intermediate 134 Off white solid Yield 19.2 mg, 5.16% HRMS (ESI⁺)calcd for [MH]⁺ of C₁₈H₁₁Cl₂N₃ 340.0408 found 340.0418. HPLC: Rt 5.17min, 100% purity. 151

5-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]-2-(1H-pyrazol-1-yl)pyridine; bis(trifluoroacetic acid) From Intermediate134 Yellow solid Yield 4.51 mg, 0.69% HRMS (ESI⁺) calcd for [MH]⁺ ofC₂₁H₁₄ClN₅ 372.1016 found 372.1025. HPLC: Rt 5.57 min, 100% purity. 152

4-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]-3- fluoropyridineFrom Intermediate 134 White solid Yield 9.24 mg, 2.61% HRMS (ESI⁺) calcdfor [MH]⁺ of C₁₈H₁₁ClFN₃ 324.0704 found 324.0710. HPLC: Rt 4.74 min,100% purity. 153

3-Chloro-4-[1-(4- chlorophenyl)-1H-pyrrolo[2,3- c]pyridin-2-yl]pyridineFrom Intermediate 134 White solid Yield 40.1 mg, 9.29% HRMS (ESI⁺) calcdfor [MH]⁺ of C₁₈H₁₁Cl₂N₃ 340.0408 found 340.0421. HPLC: Rt 4.98 min,100% purity. 154

4-[1-(4-Chlorophenyl)-1H- pyrrolo[2,3-c]pyridin-2-yl]-3- methylpyridineFrom Intermediate 134 White solid Yield 29.5 mg, 8.45% HRMS (ESI⁺) calcdfor [MH]⁺ of C₁₉H₁₄ClN₃ 320.0954 found 320.0958. HPLC: Rt 3.71 min, 100%purity.

Example 1551-Cyclopropyl-4-{1-phenyl-1H-pyrrolo[2,3-c]pyridin-2-yl}-1,2-dihydropyridin-2-one

Example 138 (50.0 mg, 0.138 mmol) was dissolved in MeOH (15 mL) andpassed through an H-cube (70×4 mm 10% Pd/C CatCart, 1.0 mL/min, 30° C.,20 bar). The solvents were removed in vacuo and the residue purified byreverse phase HPLC to give the title compound (0.610 mg, 1.35%) as acolourless gum. LCMS (ES⁺): 328.0 [MH]⁺. HPLC: Rt 4.50 min, 96.7%purity.

Biological Tests

Biological Assays of the SSAO Enzyme Inhibitors

All primary assays were performed at RT. with purified recombinantlyexpressed human SSAO. Enzyme was prepared essentially as described inOhman et al. (Protein Expression and Purification 46 (2006) 321-331). Inaddition, secondary- and selectivity assays were performed using SSAOprepared from various tissues or purified rat recombinant SSAO. Theenzyme activity was assayed with benzylamine as substrate by measuringeither benzaldehyde production, using ¹⁴C-labeled substrate, or byutilizing the production of hydrogen peroxide in a horseradishperoxidase (HRP) coupled reaction. Briefly, test compounds weredissolved in dimethyl sulfoxide (DMSO) to a concentration of 10 mM.Dose-response measurements were assayed by either creating 1:10 serialdilutions in DMSO to produce a 7 point curve or by making 1:3 serialdilutions in DMSO to produce 11 point curves. The top concentrationswere adjusted depending on the potency of the compounds and subsequentdilution in reaction buffer yielded a final DMSO concentration ≦2%.

Hydrogen Peroxide Detection:

In a horseradish peroxidase (HRP) coupled reaction, hydrogen peroxideoxidation of 10-acetyl-3,7-dihydroxyphenoxazine produced resorufin,which is a highly fluorescent compound (Zhout and Panchuk-Voloshina.Analytical Biochemistry 253 (1997) 169-174; Amplex® Red HydrogenPeroxide/peroxidase Assay kit, Invitrogen A22188). Enzyme and compoundsin 50 mM sodium phosphate, pH 7.4 were set to pre-incubate inflat-bottomed microtiter plates for approximately 15 min beforeinitiating the reaction by addition of a mixture of HRP, benzylamine andAmplex reagent. Benzylamine concentration was fixed at a concentrationcorresponding to the Michaelis constant, determined using standardprocedures. Fluorescence intensity was then measured at several timepoints during 1-2 h, exciting at 544 nm and reading the emission at 590nm. For the human SSAO assay final concentrations of the reagents in theassay wells were: SSAO enzyme 1 ug/ml, benzylamine 100 uM, Amplexreagent 20 uM, HRP 0.1 U/mL and varying concentrations of test compound.The inhibition was measured as % decrease of the signal compared to acontrol without inhibitor (only diluted DMSO). The background signalfrom a sample containing no SSAO enzyme was subtracted from all datapoints. Data was fitted to a four parameter logistic model and IC₅₀values were calculated using the GraphPad Prism 4 or XLfit 4 programs.

Aldehyde Detection:

SSAO activity was assayed using 14C-labeled benzylamine and analysed bymeasuring radioactive benzaldehyde. In a white 96-well optiplate(Packard), 20 uL of diluted test compound was pre-incubated at roomtemperature with 20 uL SSAO enzyme for approximately 15 min withcontinuous agitation. All dilutions were made with PBS. The reaction wasinitiated by adding 20 uL of the benzylamine substrate solutioncontaining [7-14C] Benzylamine hydrochloride (CFA589, GE Healthcare).The plate was incubated for 1 h as above after which the reaction wasstopped by acidification (10 uL 1M aq HCl). Then 90 uL Micro Scint-Esolution (Perkin-Elmer) was added to each well and the plate wascontinuously mixed for 15 min. Phase separation occurred instantly andactivity was read in a Topcount scintillation counter (Perkin-Elmer). Inthe final reaction well, the human recombinant SSAO concentration was 10ug/ml. In order to optimize sensitivity, the substrate concentration wasdecreased as compared to the HRP coupled assay in order to get a higherfraction of radioactive product. In the human SSAO assay, benzylamineconcentration was 40 uM (0.2 uCi/mL). Data was analysed as above.

All of the exemplified compounds of the invention had an IC₅₀ value ofbetween 1 nM and 1200 nM at SSAO (see Table 19 below).

TABLE 19 SSAO inhibitory activity (A: <50 nM, B: 50-200 nM, C: 200-1200nM) SSAO Compound IC₅₀ (nM) 1 C 2 C 3 B 4 A 5 B 6 C 7 B 8 A 9 A 10 B 11A 12 B 13 A 14 C 15 B 16 C 17 C 18 B 19 B 20 B 21 A 22 A 23 A 24 A 25 A26 B 27 A 28 B 29 C 30 C 31 C 32 A 33 C 34 B 35 C 36 B 37 A 38 B 39 A 40B 41 A 42 B 43 A 44 C 45 C 46 A 47 A 48 A 49 A 50 A 51 A 52 A 53 C 54 C55 A 56 C 57 B 58 C 59 B 60 B 61 A 62 B 63 C 64 C 65 A 66 B 67 A 68 A 69A 70 A 71 C 72 C 73 B 74 C 75 A 76 B 77 C 78 A 79 A 80 B 81 A 82 A 83 A84 A 85 A 86 A 87 A 88 A 89 A 90 A 91 C 92 A 93 B 94 C 95 B 96 B 97 C 98B 99 A 100 C 101 B 102 B 103 B 104 A 105 C 106 B 107 A 108 C 109 C 110 C111 C 112 A 113 A 114 C 115 A 116 B 117 C 118 A 119 B 120 C 121 A 122 B123 A 124 A 125 C 126 A 127 A 128 A 129 A 130 B 131 C 132 B 133 A 134 A135 A 136 A 137 A 138 A 139 A 140 A 141 B 142 B 143 A 144 B 145 A 146 B147 A 148 A 149 A 150 B 151 B 152 C 153 B 154 A 155 ChERG AssayCompounds of the invention were tested for inhibition of the human ethera go-go related gene (hERG) K⁺ channel using IonWorks patch clampelectrophysiology. 8 Point concentration-response curves were generatedon two occasions using 3-fold serial dilutions from the maximum assayconcentration (11 uM). Electrophysiological recordings were made from aChinese Hamster Lung cell line stably expressing the full length hERGchannel. Single cell ion currents were measured in the perforated patchclamp configuration (100 ug/mL amphoterocin) at room temperature usingan IonWorks Quattro instrument. The internal solution contained 140 mMKCl, 1 mM MgCl₂, 1 mM EGTA and 20 mM HEPES and was buffered to pH 7.3.The external solution contained 138 mM NaCl, 2.7 mM KCl, 0.9 mM CaCl₂,0.5 mM MgCl₂, 8 mM Na₂HPO₄ and 1.5 mM KH₂PO₄, and was buffered to pH7.3. Cells were clamped at a holding potential of 70 mV for 30 s andthen stepped to +40 mV for 1 s. This was followed by a hyperpolarisingstep of 1 s to 30 mV to evoke the hERG tail current. This sequence wasrepeated 5 times at a frequency of 0.25 Hz. Currents were measured fromthe tail step at the 5^(th) pulse, and referenced to the holdingcurrent. Compounds were incubated for 6-7 min prior to a secondmeasurement of the hERG signal using an identical pulse train. A minimumof 17 cells were required for each pIC50 curve fit. A control compound(quinidine) was used (see Table 20 below).

TABLE 20 hERG IC50 (A: >10 uM, B: 1-10 uM, C: 0.1 uM-1 uM) Compound hERGIC50 2 A 3 A 4 B 9 B 11 A 12 A 13 A 18 A 20 A 21 A 23 A 24 A 46 A 47 B48 B 50 A 51 B 52 A 53 A 54 A 57 A 63 A 64 A 67 B 69 A 70 A 71 A 75 A 77A 78 A 80 A 81 A 82 A 85 A 86 A 88 B 89 A 91 A 92 A 95 A 98 A 110 A 117A 120 B 122 B 127 C 128 A 130 C 131 B 132 C 136 B 138 B 139 C 140 B 142B 147 B 152 B 153 B

The invention claimed is:
 1. A compound of formula (Xa)

wherein E is —C═ or —N═, R⁹ and R¹⁰ are each independently one or moresubstituents selected from hydrogen, halogen, cyano, oxo, C₁₋₄-alkyl,—OC₁₋₄-alkyl, and halo-C₁₋₄-alkyl; R¹¹ is one or more substituentsselected from hydrogen, halogen, cyano, cyclopropyl, C₁₋₄-alkyl, andhalo-C₁₋₄-alkyl.
 2. A pharmaceutical composition comprising a compoundof formula (Xa)

wherein E is —C═ or —N═, R⁹ and R¹⁰ are each independently one or moresubstituents selected from hydrogen, halogen, cyano, oxo, C₁₋₄-alkyl,—OC₁₋₄-alkyl, and halo-C₁₋₄-alkyl; R¹¹ is one or more substituentsselected from hydrogen, halogen, cyano, cyclopropyl, C₁₋₄-alkyl, andhalo-C₁₋₄-alkyl; or a pharmaceutically acceptable salt thereof, and oneor more suitable excipients.
 3. A method for the treatment of a diseasewherein inhibition of SSAO activity is beneficial, which comprisesadministering to a subject suffering such disease an effective amount ofa compound of formula (Xa)

wherein E is —C═ or —N═, R⁹ and R¹⁰ are each independently one or moresubstituents selected from hydrogen, halogen, cyano, oxo, C₁₋₄-alkyl,—OC₁₋₄-alkyl, and halo-C₁₋₄-alkyl; R¹¹ is one or more substituentsselected from hydrogen, halogen, cyano, cyclopropyl, C₁₋₄-alkyl, andhalo-C₁₋₄-alkyl; or a pharmaceutically acceptable salt thereof.
 4. Thecompound of claim 1, selected from the group consisting of:4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4-methylpyridin-2-yl}morpholine(Example 21);4-{5-[3-(4-Chloro-2-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4-methylpyridin-2-yl}morpholine(Example 22);(2R,6S)-4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}-2,6-dimethylmorpholine(Example 23);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}-2,2-dimethylmorpholine(Example 24);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4-methylpyrimidin-2-yl}morpholine(Example 26);4-{5-[3-(4-Chloro-2-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4-methylpyrimidin-2-yl}morpholine(Example 27);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-6-methoxypyridin-2-yl}morpholine(Example 28);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4,6-dimethylpyridin-2-yl}morpholine(Example 29);4-{5-[3-(2,4-Difluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 41);4-{5-[3-(4-Chlorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 47);4-{5-[3-(4-Chlorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 51);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 52);4-{5-[3-(2-Fluoro-4-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 53);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 54);4-{5-[3-(4-Fluoro-2-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 55);4-{5-[3-(2-Chloro-4-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 56);4-{5-[3-(4-Methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 57);4-{5-[3-(4-Bromophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 59);4-{5-[3-(2-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 60);4-{5-[3-(2-Chloro-4-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 61);4-{5-[3-(4-Fluoro-2-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 62);4-{5-[3-(4-Methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 63);4-(5-{3-[4-(Trifluoromethyl)phenyl]-3H-imidazo[4,5-c]pyridin-2-yl}pyridin-2-yl)morpholine(Example 66);4-{5-[3-(2-Fluoro-4-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 67);4-{5-[3-(2-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 68);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}-2-methylmorpholine(Example 70);4-{5-[3-(4-Chloro-3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 74);4-{5-[3-(4-Chloro-2-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 77);4-{5-[3-(2,4-Difluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 78);4-{5-[3-(4-Chloro-2-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 80);4-(5-{3-Phenyl-3H-imidazo[4,5-c]pyridin-2-yl}pyrimidin-2-yl)morpholine(Example 95);4-{5-[3-(4-Cyclopropylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 96);4-{4-Methyl-5-[3-(4-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 97);4-{3-Fluoro-5-[3-(4-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 98);5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-2-(morpholin-4-yl)-1,4-dihydropyridin-4-one(Example 99);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-6-methylpyridin-2-yl}morpholine(Example 108);4-{5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 127);4-{5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-4-methylpyridin-2-yl}morpholine(Example 129);4-{5-[1-(4-Methylphenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 130);4-(5-{1-Phenyl-1H-pyrrolo[2,3-c]pyridin-2-yl}pyrimidin-2-yl)morpholine(Example 131);4-{5-[1-(4-Bromophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 133).
 5. The compound of claim 1, wherein the compound is4-{5-[3-(4-Methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 57).
 6. The pharmaceutical composition of claim 2, wherein thecompound is selected from the group consisting of:4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4-methylpyridin-2-yl}morpholine(Example 21);4-{5-[3-(4-Chloro-2-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4-methylpyridin-2-yl}morpholine(Example 22);(2R,6S)-4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}-2,6-dimethylmorpholine(Example 23);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}-2,2-dimethylmorpholine(Example 24);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4-methylpyrimidin-2-yl}morpholine(Example 26);4-{5-[3-(4-Chloro-2-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4-methylpyrimidin-2-yl}morpholine(Example 27);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-6-methoxypyridin-2-yl}morpholine(Example 28);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4,6-dimethylpyridin-2-yl}morpholine(Example 29);4-{5-[3-(2,4-Difluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 41);4-{5-[3-(4-Chlorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 47);4-{5-[3-(4-Chlorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 51);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 52);4-{5-[3-(2-Fluoro-4-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 53);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 54);4-{5-[3-(4-Fluoro-2-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 55);4-{5-[3-(2-Chloro-4-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 56);4-{5-[3-(4-Methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 57);4-{5-[3-(4-Bromophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 59);4-{5-[3-(2-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 60);4-{5-[3-(2-Chloro-4-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 61);4-{5-[3-(4-Fluoro-2-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 62);4-{5-[3-(4-Methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 63);4-(5-{3-[4-(Trifluoromethyl)phenyl]-3H-imidazo[4,5-c]pyridin-2-yl}pyridin-2-yl)morpholine(Example 66);4-{5-[3-(2-Fluoro-4-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 67);4-{5-[3-(2-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 68);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}-2-methylmorpholine(Example 70);4-{5-[3-(4-Chloro-3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 74);4-{5-[3-(4-Chloro-2-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 77);4-{5-[3-(2,4-Difluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 78);4-{5-[3-(4-Chloro-2-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 80);4-(5-{3-Phenyl-3H-imidazo[4,5-c]pyridin-2-yl}pyrimidin-2-yl)morpholine(Example 95);4-{5-[3-(4-Cyclopropylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 96);4-{4-Methyl-5-[3-(4-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 97);4-{3-Fluoro-5-[3-(4-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 98);5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-2-(morpholin-4-yl)-1,4-dihydropyridin-4-one(Example 99);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-6-methylpyridin-2-yl}morpholine(Example 108);4-{5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 127);4-{5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-4-methylpyridin-2-yl}morpholine(Example 129);4-{5-[1-(4-Methylphenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 130);4-(5-{1-Phenyl-1H-pyrrolo[2,3-c]pyridin-2-yl}pyrimidin-2-yl)morpholine(Example 131);4-{5-[1-(4-Bromophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 133); and pharmaceutically acceptable salts thereof.
 7. Thepharmaceutical composition of claim 1, wherein the compound is4-{5-[3-(4-Methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 57), or a pharmaceutically acceptable salt thereof.
 8. Themethod of claim 3, wherein the compound is selected from the groupconsisting of:4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4-methylpyridin-2-yl}morpholine(Example 21);4-{5-[3-(4-Chloro-2-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4-methylpyridin-2-yl}morpholine(Example 22);(2R,6S)-4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}-2,6-dimethylmorpholine(Example 23);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}-2,2-dimethylmorpholine(Example 24);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4-methylpyrimidin-2-yl}morpholine(Example 26);4-{5-[3-(4-Chloro-2-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4-methylpyrimidin-2-yl}morpholine(Example 27);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-6-methoxypyridin-2-yl}morpholine(Example 28);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-4,6-dimethylpyridin-2-yl}morpholine(Example 29);4-{5-[3-(2,4-Difluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 41);4-{5-[3-(4-Chlorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 47);4-{5-[3-(4-Chlorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 51);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 52);4-{5-[3-(2-Fluoro-4-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 53);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 54);4-{5-[3-(4-Fluoro-2-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 55);4-{5-[3-(2-Chloro-4-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 56);4-{5-[3-(4-Methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 57);4-{5-[3-(4-Bromophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 59);4-{5-[3-(2-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 60);4-{5-[3-(2-Chloro-4-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 61);4-{5-[3-(4-Fluoro-2-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 62);4-{5-[3-(4-Methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 63);4-(5-{3-[4-(Trifluoromethyl)phenyl]-3H-imidazo[4,5-c]pyridin-2-yl}pyridin-2-yl)morpholine(Example 66);4-{5-[3-(2-Fluoro-4-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 67);4-{5-[3-(2-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 68);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}-2-methylmorpholine(Example 70);4-{5-[3-(4-Chloro-3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 74);4-{5-[3-(4-Chloro-2-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 77);4-{5-[3-(2,4-Difluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 78);4-{5-[3-(4-Chloro-2-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 80);4-(5-{3-Phenyl-3H-imidazo[4,5-c]pyridin-2-yl}pyrimidin-2-yl)morpholine(Example 95);4-{5-[3-(4-Cyclopropylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 96);4-{4-Methyl-5-[3-(4-methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 97);4-{3-Fluoro-5-[3-(4-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyridin-2-yl}morpholine(Example 98);5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-2-(morpholin-4-yl)-1,4-dihydropyridin-4-one(Example 99);4-{5-[3-(4-Fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl]-6-methylpyridin-2-yl}morpholine(Example 108);4-{5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 127);4-{5-[1-(4-Chlorophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]-4-methylpyridin-2-yl}morpholine(Example 129);4-{5-[1-(4-Methylphenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 130);4-(5-{1-Phenyl-1H-pyrrolo[2,3-c]pyridin-2-yl}pyrimidin-2-yl)morpholine(Example 131);4-{5-[1-(4-Bromophenyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 133); and pharmaceutically acceptable salts thereof.
 9. Themethod of claim 3, wherein the compound is4-{5-[3-(4-Methylphenyl)-3H-imidazo[4,5-c]pyridin-2-yl]pyrimidin-2-yl}morpholine(Example 57), or a pharmaceutically acceptable salt thereof.